Cancer metastasis and recurrence remain a regular cause of postoperative death in patients, implying that extra consolidation treatment strategies are needed. Here, a cuproptosis nanoprodrug, termed as Lipo@CP@DQ NPs, is developed to initiate self-promoted cascade reactions to achieve the combinational effect of cuproptosis, in situ chemotherapy, and oxidative stress amplification for effectively suppressing tumor recurrence and metastasis after postoperative treatment. Lipo@CP@DQ NPs are fabricated by loading copper peroxides (Cu2O2, CP) and hydrogen peroxide (H2O2)-repsonsive prodrug DQ into liposomal nanoparticles. Lipo@CP@DQ NPs rapidly dissociate in the acidic tumor microenvironment to release copper ions, H2O2, and prodrug DQ. Subsequently, the excessive accumulation of Cu ions induces cuproptosis and produces highly cytotoxic hydroxyl radicals (•OH). Meanwhile, the self-supplied H2O2 catalyzes the decomposition of DQ to diethyldithiocarbamate (DTC), which is chelated with self-supplied Cu ions to form the anticancer compound, Cu(DTC)2. The another decomposition product, quinone methide (QM), acts as a glutathione (GSH) scavenger for oxidative stress amplification. The synergistic effect of Lipo@CP@DQ NPs-mediated cuproptosis, in situ chemotherapy, and oxidative stress amplification effectively inhibits the growth and postoperative recurrence of triple-negative breast cancer. This work furnishes a strategy for developing cuproptosis-based nanomedicines for effective antitumor treatment after surgery.

Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, primary resistance and acquired resistance continue to limit their efficacy for many patients. To address resistance and enhance the anti-tumor activity within the tumor immune microenvironment (TIME), numerous therapeutic strategies targeting both innate and adaptive immune cells have emerged. These include combination therapies with ICIs, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor macrophages (CAR-Ms) or chimeric antigen receptor natural killer cell (CAR-NK) therapy, colony stimulating factor 1 receptor (CSF1R) inhibitors, dendritic cell (DC) vaccines, toll-like receptor (TLR) agonists, cytokine therapies, and chemokine inhibition. These approaches underscore the significant potential of the TIME in cancer treatment. This article provides a comprehensive and up-to-date review of the mechanisms of action of various innate and adaptive immune cells within the TIME, as well as the therapeutic strategies targeting each immune cell type, aiming to deepen the understanding of their therapeutic potential.

Mitochondrial dysfunction-mediated T cell exhaustion is associated with the efficacy of tumor therapy; however, the effect of radiotherapy (RT) on the mitochondrial function of peripheral blood immune cells remains still unclear. Therefore, the current study aimed to determine mitochondrial function indicators in immune cells, in particular mitochondrial mass (MM) and mitochondrial membrane potential (MMP), to assess the dynamic changes of immune status in patients with nasopharyngeal carcinoma (NPC) during RT. Peripheral venous blood was collected from patients with locally advanced NPC at day 1 pre-RT, at the 10th fraction of RT and within 2 days after RT. Based on a novel immunofluorescence technique, flow cytometry was used to assess the proportion of lymphocytes and their subsets in peripheral blood and the mitochondrial indexes, MM and low MMP (MMPlow). Univariate and multivariate logistic regression analyses were performed to evaluate the clinical factors associated with the efficacy of RT. A total of 27 patients were enrolled. After RT, lymphocyte count (P<0.05) and the proportion of CD4+ T cells (P<0.05) demonstrated a downward trend. In addition, the proportion of CD4+ memory-effector T (Tem; P<0.05) cells and CD8+ Tem cells (P=0.005) significantly increased during RT. No significant changes were demonstrated for MM in CD4+ effector T (Te) cells, whilst MMPlow was significantly reduced (P=0.047). However, the mitochondrial function of CD8+ T cells did not significantly change. Multivariate logistic regression analysis revealed that lymphocyte count [odds ratio (OR), 47.317; 95% confidence interval (CI), 1.240-1806.065] and MMPlow in CD4+ Te cells (OR, 0.889; 95% CI, 0.792-0.997) were independent factors that could affect clinical efficacy. Receiver operating characteristic curve analysis demonstrated that the area under the curve values for MMPlow in CD4+ T cells, lymphocyte count and their combination were 0.72 (P=0.13), 0.69 (P=0.19) and 0.89 (P=0.0073), respectively. These findings suggest that RT could inhibit immune cells in peripheral blood. However, this treatment approach could activate the memory cell subsets of immune cells and enhance the MMP of effector CD4+ T cells. Therefore, the evaluation of mitochondrial function in lymphocytes could be used as a predictor of RT efficacy in patients with locally advanced NPC.

Chemotherapy combined with immunotherapy is a highly promising approach for treating tumors. However, chemotherapeutic drugs often fail to accumulate effectively at the tumor site after systemic administration and they lack sufficient immunogenicity to activate adaptive immunity, making an effective T-cell immune response within the tumor microenvironment difficult to achieve. Here, this work developed drug-loaded nanobubbles (DTX-R837@NBs) that encapsulate the chemotherapy drug docetaxel and the immune adjuvant R837 via a thin-film hydration method. Ultrasound-targeted nanobubble destruction promoted drug accumulation within tumor tissues and damaged tumor cells through the cavitation effect, inducing immunogenic cell death and releasing damage-associated molecular patterns to augment dendritic cell maturation. Notably, DTX-R837@NBs exhibited excellent contrast-enhanced ultrasound imaging capabilities, enabling the seamless integration of diagnosis and treatment. In combination with immune checkpoint blockade targeting programmed cell death protein 1 (PD-1), the generated immunological responses attacked residual tumor cells and ameliorated the immunosuppressive tumor microenvironment, inhibiting distant tumor growth and metastasis. Moreover, this strategy exhibited robust immune memory effects, effectively protecting the host and preventing tumor recurrence upon rechallenge. Overall, ultrasound-mediated DTX-R837@NBs combined with anti-PD-1 immune checkpoint blockade therapy exhibits robust antitumor efficiency, represent a promising strategy for overcoming immunotherapy resistance in cold tumors, and warrant further investigation for clinical translation.

In situ activation of prodrugs or photosensitizers is a promising strategy for specifically killing tumor cells while avoiding toxic side effects. Herein, we originally develop a bioorthogonally activatable prodrug and pro-photosensitizer system to synchronously yield an aggregation-induced emission (AIE) photosensitizer and a chemotherapeutic drug for synergistic chemo-photodynamic-immunotherapy of tumors. By employing molecular engineering strategy, we rationally design a family of tetrazine-functionalized tetraphenylene-based photosensitizers, one of which (named TzPS5) exhibits a high turn-on ratio, a NIR emission, a typical AIE character, and an excellent ROS generation efficiency upon bioorthogonal-activation. With the aid of integrin- or mitochondria-pretargeting, TzPS5 is successfully applied for highly effective PDT ablation of cancer cells both in vitro and in vivo. On this basis, tumor-targeting TzPS5 (TzPS5-cRGD) is constructed and used jointly with a bioorthogonal prodrug, DOX-TCO, and the two are mutually activated to induce cooperative and tumor-specific PDT and chemotherapy, resulting in amplified therapeutic outcomes and improved biosafeties. Moreover, this combination modality elicits robust immunogenic cell death, stimulates systemic antitumor immunity, thereby suppressing both primary and distant tumors, and blocking the pulmonary tumor metastasis. This work is expected to provide a useful guidance for the rational design of activatable phototheranostic agents, and offer a new strategy for co-activation of prodrugs/pro-photosensitizers to boost synergistic antitumor chemo-photodynamic-immunotherapy.

Autoimmune toxicity affects up to 60 % of patients receiving immune checkpoint inhibitor (ICI) therapy for cancer, presenting a notable clinical obstacle that constrains its wider application. Hence, there is an imperative demand to develop novel strategies to manage immune-related adverse events (irAEs). Ifosfamide (IFO) shares structural and functional resemblances with cyclophosphamide (CPA). Despite the acknowledged dual anti-tumor and immunomodulatory effects of CPA, the specific effect of IFO on autoimmune conditions remains elusive. Here, we evaluated the efficacy of IFO on experimental autoimmune uveitis (EAU) mouse models and explored the cell-specific effects of IFO under autoimmune conditions using single-cell RNA sequencing. Our data indicated that IFO effectively alleviated inflammatory infiltration and reversed pathological alterations of EAU. Subsequent single-cell data analysis and in vivo experiments suggested IFO exerted broad suppressive effects on autoimmune responses, concurrently restoring the balance between Th17 and Treg populations. In addition, we observed that IFO enhanced CD8+ T cell activation and its cytotoxic immune responses, highlighting the cell-type-specific immunomodulatory effects of IFO. Moreover, we constructed EAU models on tumor-bearing mice under ICI treatment, and found that ICI exacerbated EAU symptoms. IFO not only possessed anti-tumor effects as monotherapy, but also augmented ICI efficacy by promoting CD8+ T cell-mediated immunity. Furthermore, we found that IFO alleviated EAU symptoms exacerbated by ICI treatment and effectively restored Th17/Treg balance. Our results elucidated the immunomodulatory effects of IFO treatment, providing evidence for the application of IFO in managing autoimmune conditions and irAEs.

Pyroptosis has attracted significant attention for its role in cancer chemotherapy and immunotherapy. However, few drugs have been reported to induce pyroptosis via the Caspase-3/gasdermin E (GSDME) pathway. Herein, three novel PtIV prodrugs, MRP, DRP, and HRP are rationally designed by conjugating DNA methyltransferase (DNMT) inhibitor (RG108) and/or histone deacetylase (HDAC) inhibitor (PhB) to the PtIV center. These prodrugs can be easily reduced to cisplatin (CDDP) due to the high glutathione (GSH) levels in tumors, liberating the coordinated ligands. Released RG108 reactivates the GSDME gene and reduces pyroptosis in low GSDME-expressing tumor cells. Meanwhile, PhB-induced chromatin loosening enhances CDDP-DNA binding, which not only increases Caspase-3 expression, but also upregulates GSDME. HRP demonstrates superior ability to suppress tumor growth and metastasis while reducing systemic toxicity compared with CDDP. By reactivating GSDME and loosening chromatin, HRP effectively boosts tumor cell pyroptosis and exhibits the most pronounced anticancer performance. These findings highlight HRP's potential as a therapeutic agent for triple-negative breast cancer (TNBC) and offer innovative strategies for combining chemotherapy with immunotherapy. To the best of current knowledge, this is the first report of platinum complexes inducing pyroptosis via the Caspase-3/GSDME pathway in low GSDME-expressing tumor cells.

The lack of selective tumor targeting and the high toxicity of conventional chemotherapy treatments remain major challenges in cancer therapy. Here, we develop a self-controlled DNA nanostructure-CRISPR-12a system, a triple-locked cascade tumor therapy nanocapsule (Tatna), for efficient and targeted tumor treatment. Tatna integrates structural DNA tetrahedrons (DTs) with high drug-loading capacity, Cas12a/crRNA ribonucleoprotein (Cas12a RNP), and doxorubicin (DOX) to enable multisite response for precise drug delivery and augmented tumor treatment. By incorporation of a nucleolin-targeting aptamer, Tatna achieves selective targeting and efficient tumor cell internalization. Encapsulation in pH-responsive poly l-lactic-co-glycolic acid (PLGA) nanocapsule ensures stable circulation and controlled release of both DOX and Cas12a until tumor-specific activation in the acidic microenvironment. The Cas12a RNP, triggered by APE1 mRNA overexpression in tumor cells, induces trans-cleavage of DTs, releasing DOX and Cas12a to transport into the nucleus and induce enhanced cell apoptosis. This self-regulating and multifunctional approach enhances the efficacy of chemotherapy while reducing off-target effects. Tatna's programmable, tumor-specific delivery system represents a powerful strategy for advancing precision medicine and personalized cancer treatment.

Whether continuing immunotherapy after progression in second-line settings of metastatic gastric cancer (MGC) remains unclear. Herein, we explored the efficacy of PD-1 inhibitors for MGC after progression on previous chemoimmunotherapy.

We retrospectively identified MGC patients who received oxaliplatin-based chemotherapy plus PD-1 inhibitor, with or without trastuzumab, as first-line treatment. The patients received treatment with or without PD-1 inhibitors beyond progression in patients with MGC were divided into treatment beyond progression (TBP) group and non-TBP (NTBP) group. The median progression free survival (PFS) and overall survival (OS) from the start of treatment after progression were assessed.

The mOS and mPFS in the TBP group was significantly longer than that in the NTBP group (mOS: 9.0 vs. 5.0 months, P = 0.011; mPFS: 4.3 vs. 2.7 months, P = 0.03). Moreover, TBP was an independent prognostic factor for both PFS and OS in multivariate analysis. In the subgroup analysis, patients who were male, had a favorable ECOG (0-1), classified into diffuse histologic subtype and achieved disease control in the prior chemoimmunotherapy, might be more likely to benefit from continuing immunotherapy compared to discontinuation beyond progression.

PD-1 inhibitors based therapeutic strategy may be a reasonable option in second-line setting for MGC who progressed on prior immunotherapy. Further larger prospective trials are warranted to validate these findings.

Breast cancer remains one of the most prevalent malignancies worldwide, underscoring an urgent need for innovative therapeutic strategies. Immunotherapy has emerged as a transformative frontier in this context. In triple-negative breast cancer (TNBC), the combination of immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors (ICIs) with chemotherapy has proven efficacious in both early and advanced clinical trials. These encouraging results have led to the approval of ICIs for TNBC, opening up new therapeutic avenues for challenging-to-treat patient populations. Furthermore, a multitude of ongoing trials are actively investigating the efficacy of immunotherapy-based combinations, including ICIs in conjunction with chemotherapy, targeted therapy and radiation therapy, as well as other novel strategies such as bispecific antibodies, CAR-T cells and cancer vaccines across all breast cancer subtypes, including HR-positive/HER2-negative and HER2-positive disease. This review provides a comprehensive overview of current immunotherapeutic approaches in breast cancer, highlighting pivotal findings from recent clinical trials and the potential impact of these advancements on patient outcomes.

Tumor Mutation Burden (TMB) is commonly characterized as the number of non-synonymous somatic SNVs per megabase within the gene region identified through whole exon sequencing or targeted sequencing in a tumor sample. It has been statistically demonstrated that TMB was related to the ability of neoantigen production and used to predict the efficacy of immunotherapy for various types of cancers. However, screening for TMB in patients poses challenges due to the extensive labor and financial resources required for the preparation of large quantities of parallel sequencing libraries.

In this study, we employed compressed sensing (CS) to calculate TMB from overlapped pooling sequencing data, aiming to reduce the sequencing cost by minimizing the number of library builds. Over 90% SNPs could still be detected without a significant loss of mutation information even when the data is pooled from ten different samples. Based on this, the orthogonal matching pursuit (OMP) algorithm and the basic pursuit (BP) algorithm were used to reconstruct TMB from pooling sequencing data. The performance of these two algorithms was evaluated. The BP algorithm consistently performed well across all cases, albeit necessitating extended computational time. The OMP algorithm has been proved to be suitable for scenarios where the original matrix was sparse but it showed low overall performance. Based on an accurate calculation of TMB, we determined that the number of sequencing runs could be reduced to 0.6 times the total number of samples, resulting in a 40% reduction in sequencing cost.

In conclusion, we calculated TMB from overlapped pooling sequencing data utilizing compressed sensing strategy to reduce sequencing cost. Our findings confirm that the SNP calling from ten samples' pooling sequencing data is feasible. Additionally, we performed an assessment of the reconstruction efficiency of both the BP model and the OMP model.

The treatment landscape of non-small-cell lung cancer (NSCLC) is evolving rapidly, driven by advances in the development of targeted agents and immunotherapies. Despite this progress, some patients have suboptimal responses to treatment, highlighting the need for new therapeutic strategies. In the past decade, the important role of the tumour microenvironment (TME) in NSCLC progression, metastatic dissemination and response to treatment has become increasingly evident. Understanding the complexity of the TME and its interactions with NSCLC can propel efforts to improve current treatment modalities, overcome resistance and develop new treatments, which will ultimately improve the outcomes of patients. In this Review, we provide a comprehensive view of the NSCLC TME, examining its components and highlighting distinct archetypes characterized by spatial niches within and surrounding tumour nests, which form complex neighbourhoods. Next, we explore the interactions within these components, focusing on how inflammation and immunosuppression shape the dynamics of the NSCLC TME. We also address the emerging influences of patient-related factors, such as ageing, sex and health disparities, on the NSCLC-TME crosstalk. Finally, we discuss how various therapeutic strategies interact with and are influenced by the TME in NSCLC. Overall, we emphasize the interconnectedness of these elements and how they influence therapeutic outcomes and tumour progression.

The tumor microenvironment (TME) impedes the effectiveness of therapeutic strategies such as chemodynamic therapy (CDT). This study presents a novel nanoscale drug delivery system designed for the precise release of the chemotherapeutic agent doxorubicin (DOX), aiming to overcome treatment limitations, reduce systemic toxicity, and enhance antitumor efficacy. Mn(III) serves as an immunomodulatory agent, while Cu(II) regulates the levels of glutathione (GSH). Layered double hydroxides (LDHs) were synthesized and efficiently loaded with DOX, followed by surface modification with hyaluronic acid (HA). The HA-coated LDH/DOX nanocarriers showed effective internalization by tumor cells and provided a pH-responsive release of DOX. In vitro, the LDH/HA/DOX complex exhibited strong catalytic activity in the Fenton reaction. In vivo studies using an H22 hepatocarcinoma model confirmed its potent antitumor activity and excellent biocompatibility. Immunohistochemical analyses revealed that treatment with LDH/HA/DOX significantly increased infiltration of M1-polarized tumor-associated macrophages (TAMs), CD4 + T cells and CD8 + T cells, while decreasing M2-polarized TAMs. This change in immune cell profile was associated with notable tumor growth inhibition.

Detection of antigen presentation is central to understanding immunological processes and developing therapeutics for cancer, infectious diseases, and allergies. However, methods with the ability to dynamically and noninvasively distinguish between major histocompatibility complex class I (MHC-I) and MHC-II antigen presentations remain lacking. Herein, we develop activatable molecular optical reporters (MORs) for real-time differential imaging of antigen presentations in lymph nodes (LNs). These MORs are engineered to passively target LNs and activated through proteolytic cleavage by key enzymes in the MHC-I and MHC-II pathways, the immunoproteasome (iP) and cathepsin S (CTSS), respectively, triggering their chemiluminescent or fluorescent signals. Coupled with minimized signal crosstalk and high sensitivity, MORs delineate the subtle differences in the antigen presentation machinery across various disease models, including cancer and bacterial or viral infection, a feat unattainable for existing imaging methods. After systemic administration, MORs also allow real-time visualization of antigen presentation in the tumor microenvironment. Besides, MORs are validated to have potential for preclinical application in immunotherapeutics screening and clinical application in tissue biopsy. Thus, our study not only presents the first example of real-time, in vivo differential imaging of antigen presentation pathways but also opens new avenues for optical probes in immune contexture analysis.

Breast cancer (BC) remains the most prevalent malignancy among women. Clinical evidence indicates that genetic variations related to circadian rhythms, as well as the timing of therapeutic interventions, influence the response to radiation therapy and the toxicity of pharmacological treatments in women with BC. This study aimed to identify key circadian rhythm-related genes (CRGs) using bioinformatics and machine learning, and construct a prognostic model to predict clinical outcomes.

Transcriptome data for BC were retrieved from The Cancer Genome Atlas database. Univariate Cox regression and least absolute shrinkage and selection operator regression analyses were used to develop a prognostic model based on CRGs. The predictive performance of the risk score model was evaluated. Univariate and multivariate Cox regression analyses were applied to construct the prognostic model and stratify patients into high-risk and low-risk groups. Additionally, differences in immune microenvironment, immunotherapy efficacy, and tumor mutation burden were assessed between risk groups.

A prognostic risk score model comprising 17 CRGs was developed. The areas under the receiver operating characteristic curve for overall survival at 1, 3, 5, and 7 years exceeded 0.6, indicating acceptable predictive performance. Calibration plots and decision curve analyses demonstrated the use of the model in prognostic prediction. Significant differences in immune microenvironment, immunotherapy efficacy, and tumor mutation burden were identified between the low-risk and high-risk groups.

The circadian rhythm-based gene model, effectively predicted the prognosis of individuals with BC, highlighting its potential to inform personalized therapeutic strategies and improve patient outcomes.

Breast cancer presents a variety of subtypes due to its cellular and molecular heterogeneity. The capacity of cancer cells to proliferate, invade, and metastasize depends not only on their intrinsic characters but also on their dynamic interaction with the host tumor microenvironment (TME), which includes immune cells. Meanwhile, the infiltration of immune cells in the TME severely affects the occurrence, development, treatment, and prognosis of breast cancer. Therefore, this review aims to explore the immune invasive tumor microenvironment in different intrinsic subtypes of breast cancer. Additionally, it highlights the mechanistic influence of the infiltrating immune cells on stage-wise dynamics of breast tumorigenesis. Moreover, the present review also attempts to discern the regulatory relationship between tumor infiltrating immune cells and immune microenvironment in different molecular subtypes of breast cancer, thus, spotlighting its clinical significance.

Immunotherapy has transformed the neoadjuvant treatment landscape for patients with resectable locally advanced non-small cell lung cancer (NSCLC). However, a population of patients cannot obtain major pathologic response (MPR) and thus benefit less from neoadjuvant immunotherapy, highlighting the need to uncover the underlying mechanisms driving resistance to immunotherapy.

Two published single-cell RNA sequencing (scRNA-seq) datasets were used to analyze the subsets of cancer-associated fibroblasts (CAFs) and T cells and functional alterations after neoadjuvant immunotherapy. The stromal signature predicting ICI response was identified and validated using our local cohort with stage III NSCLC receiving neoadjuvant immunotherapy and other 4 public ICI transcriptomic cohorts.

Non-MPR tumors showed higher enrichment of CAFs and increased extracellular matrix deposition than MPR tumors, as suggested by bioinformatic analysis. Further, CAF-mediated immune suppression may involve reciprocal interactions with T cells in addition to a physical barrier mechanism. In contrast, MPR tumors demonstrated therapy-induced activation of memory CD8+ T cells into an effector phenotype. Additionally, neoadjuvant immunotherapy resulted in expansion of precursor exhausted T (Texp) cells, which were remodeled into an anti-tumor phenotype. Notably, we identified metabolic heterogeneity within distinct T cell clusters during immunotherapy. Methionine recycling emerged as a predictive factor for T-cell differentiation and a favorable pathological response. The stromal signature was associated with ICI response, and this association was validated in five independent ICI transcriptomic cohorts.

These discoveries underscore the distinct tumor microenvironments in MPR and non-MPR patients and may elucidate resistance mechanisms to immunotherapy in NSCLC.

Cancer is one of the leading causes of mortality worldwide. Nanomedicines have significantly improved life expectancy and survival rates for cancer patients in current standard care. However, recurrence of cancer due to metastasis remains a significant challenge. Vaccines can provide long-term protection and are ideal for preventing bacterial and viral infections. Cancer vaccines, however, have shown limited therapeutic efficacy and raised safety concerns despite extensive research. Cancer vaccines target and stimulate responses against tumor-specific antigens and have demonstrated great potential for cancer treatment in preclinical studies. However, tumor-associated immunosuppression and immune tolerance driven by immunoediting pose significant challenges for vaccine design. In situ vaccination represents an alternative approach to traditional cancer vaccines. This strategy involves the intratumoral administration of immunostimulants to modulate the growth and differentiation of innate immune cells, such as dendritic cells, macrophages, and neutrophils, and restore T-cell activity. Currently approved in situ vaccines, such as T-VEC, have demonstrated clinical promise, while ongoing clinical trials continue to explore novel strategies for broader efficacy. Despite these advancements, failures in vaccine research highlight the need to address tumor-associated immune suppression and immune escape mechanisms. In situ vaccination strategies combine innate and adaptive immune stimulation, leveraging tumor-associated antigens to activate dendritic cells and cross-prime CD8+ T cells. Various vaccine modalities, such as nucleotide-based vaccines (e.g., RNA and DNA vaccines), peptide-based vaccines, and cell-based vaccines (including dendritic, T-cell, and B-cell approaches), show significant potential. Plant-based viral approaches, including cowpea mosaic virus and Newcastle disease virus, further expand the toolkit for in situ vaccination. Therapeutic modalities such as chemotherapy, radiation, photodynamic therapy, photothermal therapy, and Checkpoint blockade inhibitors contribute to enhanced antigen presentation and immune activation. Adjuvants like CpG-ODN and PRR agonists further enhance immune modulation and vaccine efficacy. The advantages of in situ vaccination include patient specificity, personalization, minimized antigen immune escape, and reduced logistical costs. However, significant barriers such as tumor heterogeneity, immune evasion, and logistical challenges remain. This review explores strategies for developing potent cancer vaccines, examines ongoing clinical trials, evaluates immune stimulation methods, and discusses prospects for advancing in situ cancer vaccination.

Autophagy plays a crucial role in tumor drug resistance by enabling cancer cells to survive under stress conditions, including chemotherapy. It helps tumor cells maintain homeostasis, resist cell death, and contribute to therapy failure. This study analyzed the literature related to autophagy and tumor drug resistance based on the Web of Science Core Collection (WoSCC) database. The results revealed that there are 9284 relevant articles published to date, covering 103 countries and regions, with contributions from 5964 institutions and 37,240 researchers. The annual number of publications has steadily increased since 2004, especially after 2019, indicating the growing importance of autophagy in tumor drug resistance research. China leads globally in terms of publication output, accounting for nearly 50% of the total publications. Additionally, international collaboration and cross-country research have become increasingly prominent, particularly collaborations between China and countries like South Korea and Japan. Journal analysis showed that the International Journal of Molecular Sciences and Oncotarget are the most productive journals, while Autophagy stands out with a higher impact factor. Author, citation, and keyword analyses revealed research hotspots and future trends in the field of autophagy and tumor drug resistance, including chemotherapy resistance, cell death mechanisms, and immunotherapy. This study provides a systematic academic perspective for future research in the field of autophagy and tumor drug resistance and emphasizes the importance of strengthening international cooperation.

Systemic chemotherapy is a common method for treatment of metastatic lymph nodes (LNs), but it has low tissue selectivity and high toxicity. Lymphatic drug delivery system (LDDS) is a novel approach to treat and prevent LN metastases. In a previous study, it was found that the increase of osmotic pressure with varied viscosity of the drug reagent enhances drug retention in the LNs. Here, we optimized the administration conditions to achieve a long-term therapeutic response by varying the dosages and injection rate, using the optimized osmotic pressure and varied viscosity of drug reagent for LDDS. A metastatic LN mouse model was created with MXH10/Mo/lpr mice. Luciferase labelled FM3A mouse mammary carcinoma cells were inoculated in subiliac LN (SiLN) to induce metastasis to the proper axillary LN (PALN). 4 days post tumor cell inoculation, carboplatin (CBDCA) was injected into the tumor-bearing SiLN under different administration conditions. Superior drug retention was observed in the group that received two-doses of CBDCA solution adjusted to an osmotic pressure and viscosity of 1897 kPa and 12 mPa·s, at an injection rate of 10 µL/min. Furthermore, this effect persisted for 42 days. This effect was accompanied by an upregulated expression of CD8, IL-12a, and IFN-γ in the spleen. These results suggest that dual-dose administration at 10 µL/min with hyper-osmotic and high viscosity formulation is optimal and can improve the long-term therapeutic efficacy of LN metastasis.

Advances in cancer biology and drug development now enable treatments tailored to individual tumor profile. Targeting specific molecular alterations marked a significant step forward in cancer care, including breast cancer. Access to these therapies is improving thanks to the implementation of molecular tumor boards and efforts to provide molecular diagnostics at sustainable costs for all. In this context, we highlight recent progress in breast cancer therapy, focusing on biomarker-driven approaches, immunotherapy, and precision medicine paving the way for increasingly personalized and effective options.

Chemoresistance and tumor relapse remain major clinical problems. Evidence indicates that COX2/PGE2/EP axis has a critical role in tumorogenesis and chemoresistance. This study assessed the relation of the COX-2 gene expression with chemoresistance in colon cancer (CC) patients. Also, it explored the effect of chemotherapy on COX-2 expression. The study included 24 patients with CC without chemotherapeutic treatment and 24 chemoresistant CC patients. Tumor and adjacent non-neoplastic colon tissue samples were collected and COX-2 mRNA expression was measured. Also, COX-2 and its related genes; TROP2 and DUSP4 expression were analysed in 5 flurouracil and Oxalliplatin treated Caco-2 and SW-620 cells. The results indicated significant upregulation of COX-2 expression in tissues of chemoresistant CC patients when compared with that in CC tissues without chemotherapy (p < 0.001). There was a relation between COX-2 expression with lymph nodes, metastases and staging in both groups. Concerning in-vitro experiments, there was a dose dependent significant increase of COX-2, TROP2 and DUSP4 mRNA and protein expression levels in 5flurouracil and Oxalliplatin treated cells. These findings demonstrated that overexpression of COX-2 in the chemoresistant CC patients. Both 5 flurouracil and Oxalliplatin induced COX-2 overexpression and in turn COX-2 upregulation may decrease the response of cancer to chemotherapy.

Despite significant breakthroughs of therapeutic antibodies targeting PD-1 in cancer treatment, most colorectal cancer (CRC) patients respond poorly to anti-PD-1 immunotherapy. The combination therapy strategies are used to overcome the limitations mentioned above. Alistipes (A.) onderdonkii has anti-cancer effects. This study aimed to examine A. onderdonkii's effects and the related mechanisms in the anti-PD-1 treatment for CRC. In this study, anti-PD-1 therapy notably affected gut microbiota community composition in mice, particularly upregulating A. onderdonkii abundance. A. onderdonkii supplementation markedly promoted anti-PD-1 therapy's effectiveness on CRC treatment, as manifested by the elevated CD8+ T cell infiltration, promoted intestinal barrier integrity, and affected serum metabolomics. A. onderdonkii showed similar effects to the identified next-generation probiotics (NGP) Akkermansia (A.) muciniphila. Additionally, the combination therapy of anti-PD-1 and probiotics supplementation reduced PD-1 level and elevated IL-2 level, indicating that anti-PD-1 combined with A. onderdonkii efficiently restored T cell functions by inhibiting suppressive checkpoints. In conclusion, anti-PD-1 plus A. onderdonkii supplementation could account for a potential method for CRC therapy. These results provide strong evidence for A. onderdonkii as a potential NGP.

Tumor is one of the leading causes of death worldwide. The occurrence and development of tumors are related to multiple systems and factors such as the immune system, gut microbiota, and nervous system. The immune system plays a critical role in tumor development. Studies have also found that the gut microbiota can directly or indirectly affect tumorigenesis and tumor development. With increasing attention on the tumor microenvironment in recent years, the nervous system has emerged as a novel regulator of tumor development. Some tumor therapies based on the nervous system have also been tested in clinical trials. However, the nervous system can not only directly interact with tumor cells but also indirectly affect tumor development through the gut microbiota. The nervous system-mediated gut microbiota can regulate tumorigenesis, growth, invasion, and metastasis through the immune system. Here, we mainly explore the potential effects of the nervous system-gut microbiota-immune system axis on tumorigenesis and tumor development. The effects of the nervous system-gut microbiota-immune system axis on tumors involve the nervous system regulating immune cells through the gut microbiota, which can prevent tumor development. Meanwhile, the direct effects of the gut microbiota on tumors and the regulation of the immune system by the nervous system, which can affect tumor development, are also reviewed.

Immune checkpoint blockade is, as of today, the most successful form of cancer immunotherapy, with more than 43 % of cancer patients in the US eligible to receive it; however, only up to 12.5 % of patients respond to it. Similarly, adoptive cell therapy using bioengineered chimeric antigen receptorT (CAR-T) cells and T-cell receptor (TCR) cells has provided excellent responses against liquid tumours, but both forms of immunotherapy have encountered challenges within a tumour microenvironment that is both lacking in tumour-specific T-cells and is strongly immunosuppressive toward externally administered CAR-T and TCR cells. This review focuses on understanding approved checkpoint blockade and adoptive cell therapy at both biological and clinical levels before delving into how and why their combination holds significant promise in overcoming their individual shortcomings. The advent of next-generation checkpoint inhibitors has further strengthened the immune checkpoint field, and a special section explores how these inhibitors can address existing hurdles in combining checkpoint blockade with adoptive cell therapy and homing in on our cancer target for long-term immunity.

Chemoresistance is a key obstacle in the long-term survival of patients with locally and advanced lung adenocarcinoma (LUAD). This study used bioinformatic analysis to reveal the chemoresistance of gene-neutrophil extracellular traps (NETs) associated with LUAD. RNA sequencing data and LUAD expression patterns were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, respectively. The GeneCards database was used to identify NETosis-related genes (NRGs). To identify hub genes with significant and consistent expression, differential analysis was performed using the TCGA-LUAD and GEO datasets. LUAD subtypes were determined based on these hub genes, followed by prognostic analysis. Immunological scoring and infiltration analysis were conducted using NETosis scores (N-scores) derived from the TCGA-LUAD dataset. A clinical prognostic model was established and analyzed, and its clinical applications explored. Twenty-two hub genes were identified, and consensus clustering was used to identify two subgroups based on their expression levels. The Kaplan-Meier (KM) curves demonstrated statistically significant differences in prognosis between the two LUAD subtypes. Based on the median score, patients were further divided into high and low N-score groups, and KM curves showed that the N-scores were more precise at predicting the prognosis of patients with LUAD for overall survival (OS). Immunological infiltration analysis revealed significant differences in the abundances of 10 immune cell infiltrates between the high and low N-score groups. Risk scores indicated significant differences in prognosis between the two extreme score groups. The risk scores for the prognostic model also indicated significant differences between the two groups. The results provide new insights into NETosis-related differentially expressed genes (NRDEGs) associated with chemotherapy resistance in patients with LUAD. The established prognostic model is promising and could help with clinical applications to evaluate patient survival and therapeutic efficiency.

Gap junction protein B5 (GJB5, also known as Connexin 31.1) has recently been reported to be downregulated in several cancer types, where it functions primarily as a tumor suppressor in cancers such as melanoma and non-small cell lung cancer (NSCLC). However, there no reports describing its prognostic and immunological roles in pan-cancer. This study evaluated the association of GJB5 in various cancer types by a comprehensive pan-cancer analysis. The differential GJB5 expression in tumor and adjacent tissues acquired from The Cancer Genome Atlas (TCGA) databases was compared. Furthermore, univariate Cox regression and Kaplan-Meier survival analyses were performed to assess the influence of GJB5 on the disease-specific survival (DSS), disease-free interval (DFI), clinical stage, progression-free interval (PFI), and overall survival (OS) in various cancers. Moreover, the levels of GJB5 and its activity in the tumor microenvironment were assessed via the Tumor Immune Single-cell Hub (TISCH). In addition, the biological importance of GJB5 levels in various cancers was further assessed via Gene Set Enrichment Analysis. Tumor-Immune System Interactions Database (TISIDB) and Tumor Immune Estimation Resource Database 2.0 (TIMER2.0) tools indicated that GJB5 affected the tumor's immune infiltration potential. This research also evaluated the association of GJB5 with immune features: immune modulatory genes, tumor mutational burden (TMB), and microsatellite instability (MSI). The data indicated that enhanced GJB5 level was linked to worse DFI, OS, PFI, and DSS in some cancers. Additionally, GJB5 level was positively related to immune modulatory genes, TMB, immune cell infiltration, immunological checkpoints, and MSI in malignancies. Furthermore, our study demonstrated that GJB5 was upregulated in colorectal cancer tissues compared to normal tissues. We also assessed GJB5 expression across various pancreatic cell lines. Notably, GJB5 was highly expressed in pancreatic cancer cells relative to normal pancreatic epithelial cells. Additionally, GJB5 knockdown in pancreatic cancer cells resulted in a significant reduction in cell proliferation. In summary, the findings indicated the potential of GJB5 as a prospective prognostic indicator and immunological biomarker.

In cancer therapy, enhancing therapeutic indices and patient compliance has been a central focus in recent drug delivery technology development. However, achieving a delicate balance between improving anti-tumor efficacy and minimizing toxicity to normal tissues remains a significant challenge. With the advent of smart on-demand drug release strategies, new opportunities have emerged. These strategies represent a promising approach to drug delivery, enabling precise control over the release of therapeutic agents in a programmed and spatiotemporal manner. Recent studies have focused on designing delivery systems capable of releasing multiple therapeutic agents sequentially, while achieving spatial resolution in vivo. Smart on-demand drug release strategies have demonstrated considerable potential in tumor combination therapy for achieving precision drug delivery and controlled release by responding to specific physiological signals or external physical stimuli in the tumor microenvironment. These strategies not only improve tumor targeting and reduce toxicity to healthy tissues but also enable sequential release in combination therapy, allowing multiple drugs to be released in a specific spatiotemporal order to enhance synergistic treatment effects. In this paper, we systematically reviewed the current research progress of smart on-demand drug release drug delivery strategies in anti-tumor combination therapy. We highlighted representative integrated drug delivery systems and discussed the challenges associated with their clinical application. Additionally, potential future research directions are proposed to further advance this promising field.

Exportin-1 (XPO1) is a nuclear export protein that, when overexpressed, can facilitate cancer cell proliferation and survival and is frequently overexpressed or mutated in cancer patients. As such, selective inhibitors of XPO1 (XPO1i) function have been developed to inhibit cancer cell proliferation and induce apoptosis. This review outlines the evidence for the immunomodulatory properties of XPO1 inhibition and discusses the potential for combining and sequencing XPO1i with immunotherapy to improve the treatment of patients with cancer. Selinexor is a first-in-class XPO1i that is FDA-approved for the treatment of patients with relapsed and refractory (RR) multiple myeloma and RR diffuse large B cell lymphoma. In addition to the cancer cell intrinsic pro-apoptotic activity, increasing evidence suggests that XPO1 inhibition has immunomodulatory properties. In this review, we describe how XPO1i can lead to a skewing of macrophage polarisation, inhibition of neutrophil extracellular traps, modulation of immune checkpoint expression, blockade of myeloid-derived suppressor cells (MDSCs) and sensitisation of cancer cells to T cell and NK (natural killer) cell immunosurveillance. As such, there is an opportunity for selinexor to enhance immunotherapy efficacy and thus a need for clinical trials assessing selinexor in combination with immunotherapies such as immune checkpoint inhibitors, direct targeting monoclonal antibodies, chimeric antigen receptor (CAR)-T cells and cereblon E3 ligase modulators (CELMoDs).

Immunogenic cell death is a tumor cell death involving both innate and adaptive immune responses. Given the published findings that oxaliplatin causes the secretion of high mobility group box 1 (HMGB1) from cancer cells, which is necessary for the initiation of immunogenic cell death, we investigated whether oxaliplatin plays an anticancer role in gastric cancer by inducing immunogenic cell death and further explored its mechanism. We found that oxaliplatin inhibited viability and induced pyroptosis, immunogenic cell death, the production of reactive oxygen species, mitochondrial permeability transition pore (mPTP) opening, and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis activation in gastric cancer cells. Suppressing mPTP opening (cyclosporine treatment), depleting mitochondrial DNA (mtDNA; ethidium bromide treatment), or STING downregulation (H151 or si-STING treatment) reversed cGAS/STING pathway activation and the increased immunogenic cell death induced by oxaliplatin in MKN-45 and AGS cells. Moreover, oxaliplatin induced immunogenic cell death via activating the cGAS/STING/TANK-binding kinase 1 (TBK1; also known as serine/threonine-protein kinase TBK1)/interferon regulatory factor 5 (IRF5) pathway. In conclusion, oxaliplatin treatment could induce immunogenic cell death and mPTP opening and activate the cGAS/STING/TBK1/IRF5 pathway in gastric cancer cells.

Immunochemotherapy combinations have been the standard first-line therapy for advanced lung adenocarcinoma (LUAD) without driver mutations, wherein concurrent chemotherapy and immunotherapy are conventionally anchored in the established dosing regimen. A few studies have suggested that the timing of immunotherapy in combinations may have a significant impact on the efficacy. However, this issue has not been addressed in an advanced LUAD cohort. We aimed to investigate the prognostic significance of the timing of immunotherapy in first-line immunochemotherapy combinations for patients with advanced LUAD. We retrospectively analyzed 508 patients with advanced LUAD without driver mutations who received immunochemotherapy as initial systemic treatment. The patients were divided into two groups-the induction and non-induction groups-with induction defined as receiving chemotherapy alone before concurrent immunochemotherapy. The bias between different groups was minimized using propensity score matching (PSM). We found both the PFS and OS of the patients in the induction group were significantly longer than those in the non-induction group before (PFS: p < 0.0001, OS: p < 0.0001) and after PSM (PFS: p = 0.0045, OS: p = 0.00073). After adjusting for confounders, induction chemotherapy was still a significant favorable factor for both PFS (p = 0.001) and OS (p = 0.001). In subsequent analyses, we found that both ≥2-cycles induction (PFS: p = 0.000, OS: p = 0.000) and 1-cycle induction (PFS: p = 0.013, OS: p = 0.002) were superior to non-induction and these differences were still significant after PSM. Our findings highlight the notable benefits of induction chemotherapy for patients with advanced LUAD treated with first-line immunochemotherapy combinations.

Bacterial outer membrane vesicles (OMVs) have emerged as versatile nanomaterial-based drug delivery systems that can stimulate systemic immune responses and facilitate precise co-delivery of multiple therapeutic agents. This study introduces a bioengineering approach that enables the co-delivery of the angiogenesis inhibitor Angio-3 and the chemotherapeutic agent doxorubicin (DOX) within OMVs, creating a potent antitumor therapeutic platform. Angio-3 displayed on the surface of OMVs inhibited angiogenesis and decreased vascular permeability, which in turn impeded the supply of nutrients necessary for tumor growth. Moreover, intrinsic properties of OMVs triggered a systemic immune response. Both in vitro and in vivo studies, including a CT26 tumor-bearing mouse model, have demonstrated that the OMV@A&D-based therapeutic regimen, which integrates antiangiogenesis, chemotherapy, and immune activation, significantly suppresses tumor proliferation. This study highlights the potential of bioengineered OMVs in revolutionizing cancer therapy by offering a multifaceted and synergistic platform that enhances therapeutic outcomes.

Liver metastasis is the most common site of metastasis in colorectal cancer, and the prognosis of colorectal cancer patients with liver metastasis is extremely poor. Revealing the key genes of CLM and implementing targeted interventions is of great significance for colorectal cancer patients. By using the weighted gene co-expression network analysis (WGCNA) algorithm, key gene modules related to metastasis in colorectal cancer were identified. Subsequently, immune-regulating and prognostic-influencing key gene sets were identified from these modules to construct a prognostic model related to colorectal cancer metastasis. Genetic background differences underlying this model were analyzed using colorectal cancer methylation and mutation data, followed by Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) analysis of the relevant biological processes associated with the model. The value of predicting tumor drug response through the model was assessed using drug half maximal inhibitory concentration (IC50) data from colorectal cancer cell lines. Subsequently, utilizing single-cell sequencing data about liver metastasis, the colorectal cancer immune microenvironment reflected in the predictive model was analyzed, and a key gene set of the model was identified. Lastly, experimental validation was conducted to investigate the regulatory effects of photodynamic therapy (PDT) on the key genes of the model, and the cytotoxic effect of PDT on colorectal cancer was confirmed. An immune-related gene prognostic model regulating CLM was constructed, consisting of HSPA1A, ULBP2, RBP7, OXT, SLC11A1, INHBB, and ICOS. This model can predict the clinical response of colorectal cancer patients to Oxaliplatin, Cisplatin, Irinotecan, and 5-Fluorouracil. Single-cell sequencing results demonstrate that the model is associated with an immunosuppressive microenvironment in CLM. The higher the model's riskscore, the weaker the MHC-I, MHC-II, and various tumor immune signaling pathway networks in the colorectal cancer microenvironment. Causal analysis reveals that SLC11A1, ICOS, and HSPA1A play key roles in this model. PDT can kill colorectal cancer cells, inhibit colorectal cancer cell metastasis, significantly influence the expression of genes such as SLC11A1, ICOS, and HSPA1A in these processes, and suppress the infiltration of macrophages in the colorectal microenvironment, inhibiting the immune escape process of PD-1/PD-L1. A prognostic model based on immunity regulated by PDT has been established for assessing the prognosis of CLM patients, as well as clinical responses to chemotherapy drugs and immunotherapy.

Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer, some patients develop resistance to these treatments. Human epidermal growth factor receptor 2 (HER2) is overexpressed in a subset of patients with colorectal cancer and has been established as a therapeutic target.

This case report describes a Chinese patient with HER2-amplified advanced rectal cancer who showed no response to chemotherapy and targeted therapies against epidermal growth factor receptor and vascular endothelial growth factor but achieved a remarkable response following treatment with immune checkpoint inhibitors (ICIs) in combination with pyrotinib. The combination of oxaliplatin and ICIs with pyrotinib demonstrates synergistic effects after late-stage disease progression.

ICIs and pyrotinib may be effective in treating HER2-amplified advanced rectal cancer. Chemotherapy following disease progression could enhance efficacy synergistically.

Tumor protein p53 mutated/abnormal (p53abn) endometrial carcinomas account for over 50% of deaths but comprise only 15% of all endometrial carcinomas. Most patients show limited response to standard-of-care chemotherapy with or without radiotherapy, and only a minority of cases are amenable to targeted therapies like poly-ADP ribose polymerase (PARP) inhibitors and HER2-directed therapies. Recent immunotherapy clinical trials have demonstrated remarkable efficacy, not only in mismatch repair deficient (MMRd) tumors but also in a subset of mismatch repair-proficient (MMRp) tumors. However, the immune microenvironment and its relationship to other therapeutic targets in MMRp endometrial carcinoma remains poorly understood. Here, we characterize the immune microenvironment of p53abn endometrial carcinoma, the most clinically aggressive subtype of MMRp endometrial carcinoma, and correlate antitumor immune signatures with other targetable alterations. We accrued 256 treatment-naïve p53abn endometrial carcinomas and systemically profiled T-cell, B-cell, myeloid, and tumor-cell populations with multiplex immunofluorescence to assess the tissue localization and functional status of immune cells. Shallow whole-genome sequencing was performed on a subset of 126 cases. Patterns of immune infiltration were compared to survival outcomes and mutational signatures. Mixture modeling divided p53abn endometrial carcinoma into tumor-infiltrating lymphocyte (TIL)-rich and TIL-poor subsets. Over 50% of tumors were TIL-rich. TIL-rich cases overexpressed targetable immune evasion molecules and were associated with longer overall and disease-specific survival in multivariate analysis. This effect was particularly pronounced in advanced stage disease and in patients who did not receive adjuvant chemotherapy. TIL did not associate with homologous recombination deficient mutational signatures or HER2 amplification. Our findings demonstrate a biological rationale for immunotherapy in a substantial subset of patients with p53abn endometrial cancer and may help inform combination therapies with immune checkpoint inhibition, PARP inhibitors, and anti-HER2 agents. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, their efficacy in high-grade serous ovarian cancer (HGSOC) remains limited. Some patients, however, achieve lasting responses, emphasizing the need to understand how tumor microenvironment and molecular characteristics influence ICI response. The phase 2 Neo-Pembro study (NCT03126812) included 33 untreated stage IV HGSOC patients, who were scheduled for 6 cycles of carboplatin-paclitaxel and interval cytoreductive surgery. Pembrolizumab (pembro) was added from cycle two and continued for one year. The primary objective was to assess intratumoral immune activation using multiplexed immunofluorescence and immune-related gene expression. Our findings show immune activation, evidenced by an increase in CD3 + , CD8 + , CD8 + /FOXP3+ ratio, TNF-α and interferon-γ signaling. Treatment was well-tolerated. We observed major pathologic responses in 9/33 patients (27%, 95%CI 14-46), with pathologic response strongly associated with immune activation and OS. At a median follow-up of 52.8 months, 8/9 major responders were alive, with 6 patients recurrence-free. In contrast, 4/24 minor responders survived, including one recurrence-free. ctDNA clearance was observed in all major responders and was associated with prolonged PFS and OS. PD-L1 expression and homologous recombination deficiency were predictive of major response and may serve as biomarkers, warranting further exploration. These results suggest major responders may benefit from neo-adjuvant pembro.

The mitochondrial solute carrier family 25 (SLC25) is known to play a pivotal role in oncogenesis, yet its specific involvement in hepatocellular carcinoma (HCC) remains poorly elucidated.

In this study, we performed a clustering analysis of HCC patients in the Cancer Genome Atlas database based on the expression levels of SLC25 members, and conducted clinical feature analysis for each patient within the clusters. Subsequently, we developed a prognostic model using a Lasso regression approach with SLC25A19, SLC25A49, and SLC25A51 as features, and generated a risk score for each HCC patient. We then identified SLC25A19 as a potential prognostic marker for HCC through single-cell analysis, and validated this finding using in vitro and in vivo experiments.

Our results revealed significant differences in the expression of most SLC25 family members in HCC patients, enabling the stratification of patients into three clusters, with those in cluster 1 exhibiting the most favorable prognosis and showing a correlation with enhanced immune infiltration. The risk scores derived from the features SLC25A19, SLC25A49, and SLC25A51 effectively predicted the prognosis of HCC patients, with area under the curve (AUC) values exceeding 0.7 in the test group. Single-cell analysis further demonstrated h eightened expression of SLC25A19 in the immune microenvironment of HCC, and in vitro experiments indicated that SLC25A19 may regulate the proliferation, migration, invasion, cycle, and apoptosis of liver cancer cells through the Wnt pathway. In the HepG2 animal model, overexpression of SLC25A19 significantly promotes tumor growth, while knockdown inhibits tumor growth. Analysis of patient tumor tissues shows that SLC25A19 is highly expressed in liver cancer tissues and is associated with CD8+ T cell infiltration.

In conclusion, our comprehensive analysis of the role of SLC25 in HCC unveiled SLC25A19 as a potential regulatory factor in HCC.

Human papillomavirus (HPV)-related lower genital cancers, including cervical cancer, anal squamous cell carcinoma (SCC), vaginal cancer, vulvar cancer, and penile cancer, pose a significant health burden, with approximately 45,000 new cases diagnosed annually. Current effective treatment modalities include chemoradiotherapy, systemic chemotherapy, and immune checkpoint inhibitors (ICIs). The tumor microenvironment in HPV-related cancers is characterized by immune evasion mechanisms, including the modulation of immune checkpoints such as PD-L1/PD-1. HPV oncoproteins E5, E6, and E7 play crucial roles in this process, altering the expression of immune inhibitory molecules and the recruitment of immune cells. ICIs, such as programmed cell death protein 1 (PD-1) inhibitors, have shown efficacy in enhancing the immune response against HPV-associated tumors by blocking proteins that allow cancer cells to evade immune surveillance. Recent studies have demonstrated that HPV-positive tumors exhibit a more favorable response to ICI-based therapies compared to HPV-negative tumors. The integration of ICIs into treatment regimens for HPV-related cancers has been supported by several clinical trials. The inclusion of ICIs in the treatment approach for HPV-related lower genital cancers presents a promising opportunity for improving patient outcomes. Ongoing research and clinical trials are advancing our understanding of the immune microenvironment and the therapeutic potential of immunotherapy for these cancers.

This study examines the roles of Cyclin B1 (CCNB1), Polo-Like Kinase 1 (PLK1), and Heparanase (HPSE) in breast cancer progression using a multi-omics approach. These genes are known for their involvement in various cancer-related processes, but their precise contributions to breast cancer remain unclear.

We employed an integrative analysis combining transcriptomics, proteomics, DNA methylation profiling, immune infiltration analysis, and single-cell RNA sequencing to investigate the expression patterns, regulatory mechanisms, and functional impacts of CCNB1, PLK1, and HPSE in breast cancer. Functional assays using si-RNA knockdown of CCNB1 and PLK1 were performed to assess their roles in cell proliferation.

CCNB1, PLK1, and HPSE are upregulated in breast tumors at the mRNA and protein levels. CCNB1 and PLK1 promote tumor growth and metastasis, while HPSE is linked to immune pathways. DNA methylation in BRCA correlates with prognosis, with PLK1 alterations protective for recurrence-free survival. High expression of these genes worsens prognosis, with CCNB1 as a risk factor for overall survival. Immune infiltration analysis associates these genes with tumor-infiltrating immune cells, highlighting HPSE's immunotherapeutic potential. Single-cell RNA sequencing confirms CCNB1 and PLK1 drive malignant proliferation and an immunosuppressive environment. Functional assays demonstrated that silencing CCNB1 and PLK1 significantly reduced breast cancer cell proliferation, indicating regulatory interactions among PLK1, CCNB1, and MKI67.

This study provides evidence that CCNB1, PLK1, and HPSE are key players in breast cancer progression and potential biomarkers for prognosis. Furthermore, their roles in immune regulation suggest they could be promising targets for immunotherapy.

Flavonoids are a group of polyphenolic compounds distributed in vegetables, fruits and other plants, which have considerable antioxidant, anti‑tumor and anti‑inflammatory activities. Several types of gastrointestinal (GI) cancer are the most common malignant tumors in the world. A large number of studies have shown that flavonoids have inhibitory effects on cancer, and they are recognized as a class of potential anti‑tumor drugs. Therefore, the present review investigated the molecular mechanisms of flavonoids in the treatment of different types of GI cancer and summarized the drug delivery systems commonly used to improve their bioavailability. First, the classification of flavonoids and the therapeutic effects of various flavonoids on human diseases were briefly introduced. Then, to clarify the mechanism of action of flavonoids on different types of GI cancer in the human body, the metabolic process of flavonoids in the human body and the associated signaling pathways causing five common types of GI cancer were discussed, as well as the corresponding therapeutic targets of flavonoids. Finally, in clinical settings, flavonoids have poor water solubility, low permeability and inferior stability, which lead to low absorption efficiency in vivo. Therefore, the three most widely used drug delivery systems were summarized. Suggestions for improving the bioavailability of flavonoids and the focus of the next stage of research were also put forward.