In human beings heterogenous, pervasive and lethal malignancies of different parts of the gastrointestinal (GI) tract viz., tumours of the oesophagus, stomach, small intestine, colon, and rectum, represent gastrointestinal malignancies. Primary treatment modality for gastric cancer includes chemotherapy, surgical interventions, radiotherapy, monoclonal antibodies and inhibitors of angiogenesis. However, there is a need to improve upon the existing treatment modality due to associated adverse events and the development of resistance towards treatment. Additionally, age has been found to contribute to increasing the incidence of tumours due to immunosenescence-associated immunosuppression. Immunosenescence is the natural process of ageing, wherein immune cells as well as organs begin to deteriorate resulting in a dysfunctional or malfunctioning immune system. Accretion of senescent cells in immunosenescence results in the creation of a persistent inflammatory environment or inflammaging, marked with elevated expression of pro-inflammatory and immunosuppressive cytokines and chemokines. Perturbation in the T-cell pools and persistent stimulation by the antigens facilitate premature senility of the immune cells, and senile immune cells exacerbate inflammaging conditions and the inefficiency of the immune system to identify the tumour antigen. Collectively, these conditions contribute positively towards tumour generation, growth and eventually proliferation. Thus, activating the immune cells to distinguish the tumour cells from normal cells and invade them seems to be a logical strategy for the treatment of cancer. Consequently, various approaches to immunotherapy, viz., programmed death ligand-1 (PD-1) inhibitors, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors etc are being extensively evaluated for their efficiency in gastric cancer. In fact, PD-1 inhibitors have been sanctioned as late late-line therapy modality for gastric cancer. The present review will focus on deciphering the link between the immune system and gastric cancer, and the alterations in the immune system that incur during the development of gastrointestinal malignancies. Also, the mechanism of evasion by tumour cells and immune checkpoints involved along with different approaches of immunotherapy being evaluated in different clinical trials will be discussed.

Immunotherapeutics against triple-negative breast cancer (TNBC) hold great promise. In this work, we provide a combination therapy for simultaneous increasing tumor immunogenicity and down-regulating programmed cell death ligand 1 (PD-L1) to boost antitumor immunity in TNBC. We prepare bis (diethyldithiocarbamate)-copper/indocyanine green nanoparticles (CuET/ICG NPs) simply in aqueous with one-pot method. CuET/ICG NPs interfere mitochondria, reduce oxygen consumption, and alleviate tumor hypoxia to potentiate photodynamic therapy (PDT) for amplifying immunogenic cell death (ICD). Meanwhile, mitochondria dysfunction leads to energy stress and activates AMPK pathway. As a result, CuET/ICG NPs downregulates membrane PD-L1 (mPD-L1) on both 4T1 cancer cells and cancer stem cells (CSCs) through AMP-activated protein kinase (AMPK)-mediated pathway in hypoxia. Cooperatively, the combinational therapy activates antitumor immunity and triggers long lasting immune memory response to resist tumor re-challenge. Our study represents an attempt that conquers tumor immunosuppressive microenvironment with simple biomedical materials and multimodality treatments.

Endometrial cancer (EC) is a prevalent gynecologic cancer, with worldwide increasing incidence and disease-associated mortality. N-glycosylation, a critical post-translational modification, has been implicated in cancer progression and immune response modulation. We aimed to elucidate the role of N-glycosylation-related genes on EC cell heterogeneity, prognosis, and immunotherapy response.

Data from single-cell RNA sequencing (scRNA) of five patients with EC were acquired from the Gene Expression Omnibus (GEO) database. Nonnegative matrix factorization (NMF) was used to identify cell subtypes related to N-glycosylation from a scRNA matrix. Subsequently, a consensus prognostic signature by integrating 101 combinations of 10 machine learning algorithms. The response to immunotherapy in EC was further examined by multiple algorithms.

Our findings identified 11,020 differentially expressed genes (DEGs), of which 34 N-glycosylation-related DEGs were remarkably associated with overall survival (OS) in EC. Single-cell RNA sequencing analysis revealed 30,233 cells divided into eight clusters, with T cells and epithelial cells showing distinct functional characteristics. NMF clustering further classified malignant cells into four subtypes: N-glycosylation-C0, Glycosphingolipid-C1, O-GalNAc-C2, and Elongation-C3. The O-GalNAc-C2 subtype exhibited the highest metabolic pathway activity and activation of transcription factors SOX4, JUND, and FOS. Additionally, cell-cell interaction networks highlighted the MK signaling pathway as a critical mediator of intercellular communication. An integrated machine learning framework generated a prognostic model comprising eight DEGs (LAMC2, KRT7, IL32, KRT18, SERPINA1, PGR, AKAP12, EDN2), achieving an average C-index of 0.712 in training and validation cohorts. A low-risk score implies more significant immune cell infiltration and better response to immunotherapy.

Our study underscores the role of N-glycosylation-related genes in EC prognosis and immunotherapy response prediction, and may provide a basis for the development of targeted therapies and personalized treatment strategies.

Autoantibodies (Aab) are recognized as key indicators in the diagnosis, classification, and monitoring of systemic autoimmune diseases (AID). Recent studies have expanded knowledge through the discovery of new antigenic targets, advanced methods for measuring Aab levels, and understanding their possible pathogenic roles in AID. This narrative review uses systemic sclerosis (SSc) as an example to highlight the importance of Aab associated with HEp-2 immunofluorescence assay positivity (traditionally referred as antinuclear antibodies [ANA]), exploring recent developments in the field. Firstly, we outline the various types of ANA found in SSc and their links with specific disease features. Newly discovered antibodies shed light on SSc cases where Aab had previously gone unidentified. Secondly, we emphasize the necessity for novel quantitative techniques to track Aab levels over time by gathering data regarding the timing of Aab occurrence relative to SSc symptoms and the relationships between Aab concentrations and disease severity. Finally, we discuss the experimental findings suggesting a potential direct role of Aab in the development of SSc. The advancements surrounding Aab provide insights into new disease mechanisms and may lead to innovative diagnostic and treatment approaches.

T cells and their T cell receptors (TCRs) play crucial roles in the adaptive immune system's response against pathogens and tumors. However, immunosenescence, characterized by declining T cell function and quantity with age, significantly impairs antitumor immunity. Recent years have witnessed remarkable progress in T cell-based cancer treatments, driven by a deeper understanding of T cell biology and innovative screening technologies. This review comprehensively examines T cell maturation mechanisms, T cell-mediated antitumor responses, and the implications of thymic involution on T cell diversity and cancer prognosis. We discuss recent advances in adoptive T cell therapies, including tumor-infiltrating lymphocyte (TIL) therapy, engineered T cell receptor (TCR-T) therapy, and chimeric antigen receptor T cell (CAR-T) therapy. Notably, we highlight emerging DNA-encoded library technologies in mammalian cells for high-throughput screening of TCR-antigen interactions, which are revolutionizing the discovery of novel tumor antigens and optimization of TCR affinity. The review also explores strategies to overcome challenges in the solid tumor microenvironment and emerging approaches to enhance the efficacy of T cell therapy. As our understanding of T cell biology deepens and screening technologies advances, T cell-based immunotherapies show increasing promise for delivering durable clinical benefits to a broader patient population.

While neoadjuvant chemotherapy combined with surgical resection has improved the prognosis for patients with osteosarcoma, its impact on metastatic and recurrent cases remains limited. Immunotherapy is emerging as a promising alternative. However, the relationship between the phenotype of tumor-associated macrophages and the prognosis of osteosarcoma remains unclear. Differentially expressed gene during macrophage polarization were identified using the Monocle package. Weighted gene co-expression network analysis was conducted to select genes regulating macrophage polarization. The least absolute shrinkage and selection operator algorithm and multivariate Cox regression were used to construct long-term survival predictive strategies. Multiple machine learning algorithms identified target genes for pan-cancer analysis. Lentiviral transfection created stable strains with target gene knockdown, and CCK-8 and transwell migration assays verified the target gene's effects. Western blot and flow cytometry assessed the impact of target genes on macrophage polarization. A total of 141 genes regulating macrophage polarization were identified, from which eight genes were selected to construct prognostic models. Significant differences between high-risk and low-risk groups were observed in immune cell activation, immune-related signaling pathways, and immune function. The prognostic model and target gene were validated to provide more precise immunotherapy options for osteosarcoma and other tumors. BNIP3 knockdown decreased osteosarcoma cell proliferation and migration and promoted macrophage polarization to the M2 phenotype. The constructed prognostic model offers precise immunotherapy regimens and valuable insights into mechanisms underlying current studies. Furthermore, BNIP3 may serve as a potential immunotherapeutic target for osteosarcoma and other tumors.

Cancer-related deaths continue to rise, largely due to the suboptimal efficacy of current treatments. Fortunately, immunotherapy has emerged as a promising alternative, offering new hope for cancer patients. Among various immunotherapy approaches, targeting tumor-specific antigens (TSAs) has gained particular attention due to its demonstrated success in clinical settings. Despite these advancements, there are still gaps in our understanding of TSAs. Therefore, this review explores the life cycle of TSAs in cancer, the methods used to identify them, and recent advances in TSAs-targeted cancer therapies. Enhancing medical professionals' understanding of TSAs will help facilitate the development of more effective TSAs-based cancer treatments.

Cancer immunotherapy, encompassing both experimental and standard-of-care therapies, has emerged as a promising approach to harnessing the immune system for tumor suppression. Experimental strategies, including novel immunotherapies and preclinical models, are actively being explored, while established treatments, such as immune checkpoint inhibitors (ICIs), are widely implemented in clinical settings. This comprehensive review examines the historical evolution, underlying mechanisms, and diverse strategies of cancer immunotherapy, highlighting both its clinical applications and ongoing preclinical advancements. The review delves into the essential components of anticancer immunity, including dendritic cell activation, T cell priming, and immune surveillance, while addressing the challenges posed by immune evasion mechanisms. Key immunotherapeutic strategies, such as cancer vaccines, oncolytic viruses, adoptive cell transfer, and ICIs, are discussed in detail. Additionally, the role of nanotechnology, cytokines, chemokines, and adjuvants in enhancing the precision and efficacy of immunotherapies were explored. Combination therapies, particularly those integrating immunotherapy with radiotherapy or chemotherapy, exhibit synergistic potential but necessitate careful management to reduce side effects. Emerging factors influencing immunotherapy outcomes, including tumor heterogeneity, gut microbiota composition, and genomic and epigenetic modifications, are also examined. Furthermore, the molecular mechanisms underlying immune evasion and therapeutic resistance are analyzed, with a focus on the contributions of noncoding RNAs and epigenetic alterations, along with innovative intervention strategies. This review emphasizes recent preclinical and clinical advancements, with particular attention to biomarker-driven approaches aimed at optimizing patient prognosis. Challenges such as immunotherapy-related toxicity, limited efficacy in solid tumors, and production constraints are highlighted as critical areas for future research. Advancements in personalized therapies and novel delivery systems are proposed as avenues to enhance treatment effectiveness and accessibility. By incorporating insights from multiple disciplines, this review aims to deepen the understanding and application of cancer immunotherapy, ultimately fostering more effective and widely accessible therapeutic solutions.

Breast cancer represents the most prevalent cancer among women globally, constituting approximately 30% of newly diagnosed female malignancies and serving as the second leading cause of cancer-related mortality, accounting for 11.6% of deaths. Despite notable advancements in survival rates and quality of life for breast cancer patients over recent decades-achieved through interventions such as surgery, chemotherapy, radiotherapy, and endocrine therapy-there remains an urgent need for novel therapeutic strategies. This necessity arises from challenges associated with recurrence, metastasis, and drug resistance. The COVID-19 pandemic has accelerated the development of Messenger RNA (mRNA) vaccines at an unprecedented pace, and as a novel form of precision immunotherapy, mRNA vaccines are increasingly being recognized for their potential in cancer treatment. mRNA vaccines efficiently produce antigens within the cytoplasm, specifically activating the immune system to target tumor cells while minimizing the risk of T-cell tolerance. Therefore, mRNA vaccines have emerged as a promising approach in cancer immunotherapy. This review systematically examines the principles, mechanisms, advantages, key targets, and recent progress in mRNA vaccine therapy for breast cancer. Furthermore, it discusses current challenges and suggests potential directions for future research.

Oxysterol-binding proteins (OSBPs), lipid transfer proteins functioning at intracellular membrane contact sites, are recently found to be dysregulated in cancer and promote cancer cell survival. However, their role as potential targets in cancer therapy remains largely unexplored. In this study, we found OSW-1, a natural compound and OSBP inhibitor, potently and selectively kills colon cancer cells by activating a previously unknown necroptosis pathway that is independent of receptor-interacting protein 1 (RIP1) and RIP3. OSW-1 stabilizes p53 and degrades OSBPs to promote endoplasmic reticulum (ER) stress and glycogen synthase kinase 3β (GSK3β)/Tip60-mediated p53 acetylation at Lysine 120, which selectively induces its target PUMA. PUMA-mediated mitochondrial calcium influx activates calcium/calmodulin-dependent protein kinase IIδ (CamKIIδ) to promote mixed lineage kinase domain-like (MLKL) phosphorylation and necroptotic cell death. Furthermore, OSW-1-induced necroptosis is highly immunogenic and sensitizes syngeneic colorectal tumors to anti-PD-1 immunotherapy. Together, our results identified a novel RIP1/RIP3-independent necroptosis pathway underlying the extremely potent anticancer activity of OSW-1, which can be harnessed to develop new anticancer therapies by selectively stimulating antitumor immunity.

Cisplatin (DDP) resistance presents a major challenge in bladder cancer (BLCA) treatment. Recent evidence suggests that Astragalus polysaccharide (APS), extracted from Astragalus membranaceus, may sensitize tumors to DDP. However, the precise mechanisms by which APS modulates DDP sensitivity in BLCA are not fully elucidated. The study employed computational biology, bioinformatics, and both in vitro and in vivo experiments to explore the role of APS in BLCA. The results demonstrate that APS inhibits BLCA cell proliferation, induces apoptosis in vitro, and suppresses tumor growth in vivo. Additionally, APS induces G0/G1 cell cycle arrest in BLCA cells by downregulating CCND1 expression. Moreover, APS further enhances DDP-induced apoptosis by downregulating PI3K-p110β and p-AKT expression, while upregulating FoxO1 expression. Bioinformatics analysis indicates that APS may remodel the tumor microenvironment (TME) and influence cell-cell interactions, specifically through modulation of macrophage M2 polarization and CD8+ T cell exhaustion, thereby overcoming DDP resistance. In conclusion, APS potentiates DDP-induced apoptosis in BLCA cells via the PI3K/AKT/FoxO1 axis and may act as an immunomodulator to remodel the TME, offering a potential strategy to combat DDP resistance in BLCA.

Oral Cancer is one of the most prevalent malignant tumors of the head and neck. The three primary clinical treatments available till now for oral cancer are chemotherapy, radiation, and surgery. The goal of this review was to outline the basic principles of immunotherapy along with various immunotherapeutic agents on Oral Squamous Cell Carcinoma.

A comprehensive search in PubMed, Scopus, and Google Scholar was performed using relevant keywords. All the articles, both English as well as non-English were included also with inclusion data from high-incidence countries (South-east Asia) and the compilation was ten done after getting the data reviewed from two pathologists who were blinded to the data.

All the data has been compiled and the various sections in the manuscript provides an insight into the current trends in immunotherapy.

Advanced research studies are needed to counteract the hurdles associated with immunotherapy so that a greater proportion of patients can be treated.

One of the more recent developments that is promising is immunotherapy, which can be quite beneficial when used as a monotherapy or an adjuvant treatment. This more recent treatment approach could serve as the fourth pillar in cancer care, alongside radiation, chemotherapy, and surgery. Because immunotherapy relies on the patient's immunological environment, careful patient selection is essential to its effectiveness.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that typically lacks effective targeted therapies, leading to limited treatment options. Chemotherapy remains the primary treatment modality; however, in recent years, new immunotherapy approaches, such as immune checkpoint inhibitors, have shown positive results in some patients. Although the development of TNBC is closely associated with BRCA gene mutations, the tumor immune microenvironment (TIME) plays a crucial role in tumor progression and immune escape. Tumor angiogenesis, the accumulation of immunosuppressive cells, and alterations in immune molecules collectively shape an environment unfavorable for anti-tumor immune responses. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) promote immune escape by secreting immunosuppressive factors. Therefore, combination strategies of anti-angiogenic and immune checkpoint inhibitory therapies have shown synergistic effects in clinical trials, while new targeted therapies such as TGF-β inhibitors and IL-1β inhibitors offer new options for TNBC treatment. With the development of personalized medicine, combining immunotherapy and targeted therapies brings new hope for TNBC patients.

Cancer immunotherapy has transformed oncology by harnessing the immune system to specifically target cancer cells, offering reduced systemic toxicity compared to traditional therapies. This review highlights key strategies, including adoptive cell transfer (ACT), immune checkpoint inhibitors, oncolytic viral (OV) therapy, monoclonal antibodies (mAbs), and mRNA-based vaccines. ACT reinfuses enhanced immune cells like tumor-infiltrating lymphocytes (TILs) to combat refractory cancers, while checkpoint inhibitors (eg, PD-1 and CTLA-4 blockers) restore T-cell activity. OV therapy uses engineered viruses (eg, T-VEC) to selectively lyse cancer cells, and advanced mAbs improve targeting precision. mRNA vaccines introduce tumor-specific antigens to trigger robust immune responses. Despite significant progress, challenges like immune-related side effects, high costs, and immunosuppressive tumor microenvironments persist. This review underscores the need for combination strategies and precision medicine to overcome these barriers and maximize the potential of immunotherapy in personalized cancer treatment.

Tumor metabolism often interferes with the immune microenvironment. Although natural killer (NK) cells play pivotal roles in antitumor immunity, the connection between NK cells and tumor metabolism remains unclear. Our systematic analysis of multiomics data and survival data from colorectal cancer (CRC) patients uncovered a novel association between mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) and NK cell infiltration that influences disease progression. ACAT1, a metabolic enzyme involved in reversible conversion of acetoacetyl-CoA to two molecules of acetyl-CoA, exhibits nuclear protein acetylation activity through its translocation. Under immune stimulation, mitochondrial ACAT1 can be phosphorylated at serine 60 (S60) and enters the nucleus; however, this process is hindered in nutrient-poor tumor microenvironments. Nuclear ACAT1 directly acetylates lysine 146 of p50 (NFKB1), attenuating its DNA binding and transcriptional repression activity and thereby increasing the expression of immune-related factors, which in turn promotes NK cell recruitment and activation to suppress colorectal cancer growth. Furthermore, significant associations are found among low nuclear ACAT1 levels, decreased S60 phosphorylation, and reduced NK cell infiltration, as well as poor prognosis in CRC. Our findings reveal an unexpected function of ACAT1 as a nuclear acetyltransferase and elucidate its role in NK cell-dependent antitumor immunity through p50 acetylation.

CXC chemokines are a class of cytokines possessing chemotactic properties. Studies indicate that CXC chemokines exhibit dysregulation in miscellaneous cancer categories and are significantly associated with the advancement of tumors. Breast cancer is a commonly diagnosed and fatal cancer among the female population. Breast cancer pathogenesis and progression involve various mechanisms, including invasion, metastasis, angiogenesis, and inflammation. Chemokines and their receptors are involved in all of these processes. The CXC chemokine receptors (CXCRs) and their related ligands have attracted considerable attention due to their multifaceted functions in facilitating and controlling tumor proliferation. CXCRs are expressed by both cancer cells and immune cells, and they play a crucial role in regulating the tumor microenvironment and the immune response. This review aims to assess the potential of CXCRs and CXC chemokines as therapeutic targets or biomarkers for personalized therapy. Additionally, it provides an overview of the current understanding of the expression, function, and prognostic relevance of CXCRs in breast cancer. Furthermore, the challenges and potential prospects pertaining to CXCR investigation in breast cancer are deliberated.

Pancreatic ductal adenocarcinoma (PDAC) is challenging to treat due to its immunosuppressive tumor microenvironment (TME) and resistance to immune checkpoint inhibitors. This study aims to discover new therapeutic targets and predictive biomarkers for PDAC.

Using Mendelian randomization, we studied causal relationships between PDAC and an array of immune cell traits, bacterial traits, inflammatory factors, and blood metabolites. We employed large genome-wide association study datasets and the two-sample MR approach for the investigation.

Our results highlight suggestive evidence of associations between PDAC and distinct immune cell phenotypes, revealing nuanced alterations across monocytes, T-cells, B-cells, dendritic cells, and myeloid-derived suppressor cells. Our study provides a granular view of the PDAC-immune interface, identifying key immune cell traits and their associations with PDAC. For instance, our findings suggest a detrimental reduction in various monocyte traits, alongside a decrease in B-cell populations. Conversely, certain T-cell subsets showed increased associations, indicating potential targets for immunotherapeutic strategies. The bacterial trait associations, particularly with Collinsella and Ruminococcus torques, highlight the gut microbiome's influence on immune modulation and PDAC pathogenesis. Additionally, the traits concerning Interleukin-12 subunit beta levels and T-cell surface glycoprotein CD5 levels further indicate their function of this complex interaction.

This study enhances our understanding of PDAC's resistance to immunotherapies and highlights the potential of personalized immunotherapy and metabolic pathway modulation in PDAC treatment. Our findings provide supportive evidence for research and clinical translation.

The introduction of immunotherapy and target therapy into clinical practice has become a chance for many patients with cancer to prolong their survival while maintaining optimal quality of life. Treatment of lung cancer is excellent evidence of the progress of medical therapies. An understanding of the mechanisms of tumor development has led to the evolution of new methods of treatment. Immunoreceptors of T cells with the immunoglobulin domain ITIM, TIM-3 (T-cell immunoglobulin- and mucin domain-3-containing molecule 3), and LAG-3 (lymphocyte activation gene-3) represent new interesting therapeutic targets. The combination of anti-PD-1 and anti-CTLA-4 blockade has proven the possibility of strengthening the anti-tumor response by acting via two separate mechanisms. Adding additional checkpoints to the PD-1 blockade offers hope for further improvements in the effects of the treatment of patients and expanding the group responding to immunotherapy. This paper presents new promising molecular targets along with studies demonstrating the treatment results using them.

This short perspective presents, at a high level, some observations and speculations about cancer immunotherapy that derive from experiences at the Dana-Farber Cancer Institute and the Novartis Institutes of Biomedical Research.

Cholesterol is a unique lipid for all mammalian cells, with important functions in membrane biogenesis and maintenance of proper membrane integrity and fluidity. Therefore, it plays an important role in cellular homeostasis. Dysregulation of cholesterol homeostasis is associated with various diseases in humans, including cardiovascular diseases, inflammatory diseases, neurodegenerative disorders, and cancers. In the tumor microenvironment, intrinsic and extrinsic cellular factors reprogram cholesterol metabolism and consequently promote tumorigenesis. Here, we summarize the current knowledge on molecular mechanisms and functional roles of cholesterol homeostasis and its dysregulation in regard to cancer pathogenesis. We also discuss the interplay of cholesterol metabolism and the ATP-binding cassette (ABC) proteins, highly conserved cellular transmembrane lipid transporters. An emerging role of lipid ABC transporters as potential prognostic tools for cancer progression and invasiveness is emphasized. Targeting both cholesterol metabolism and proteins associated with membrane cholesterol holds promise as a novel therapeutic strategy for cancer treatment.

Cancer-associated fibroblasts (CAFs) are integral components of the tumor microenvironment playing key roles in tumor progression, metastasis, and therapeutic resistance. However, challenges persist in understanding their heterogeneity, origin, and functional diversity. One major obstacle is the lack of standardized naming conventions for CAF subpopulations, with current systems failing to capture their full complexity. Additionally, the identification of CAFs is hindered by the absence of specific biomarkers, limiting the precision of diagnostic and therapeutic strategies. In vitro culture conditions often fail to maintain the in vivo characteristics of CAFs, which complicates their study and the translation of findings to clinical practice. Although current detection methods, such as antibodies, mRNA probes, and single-cell transcriptomics, offer insights into CAF biology, they lack standardization and fail to provide reliable quantitative measures. Furthermore, the dynamic interactions between CAFs, tumor cells, and immune cells within the TME remain insufficiently understood, and the role of CAFs in immune evasion and therapy resistance is an area of ongoing research. Understanding how CAFs influence drug resistance and the immune response is essential for developing more effective cancer therapies. This review aims to provide an in-depth analysis of the challenges in CAF research, propose future research directions, and emphasize the need for improved CAF-targeted therapeutic strategies. By addressing these gaps, it seeks to highlight the potential of CAFs as targets for overcoming therapeutic resistance and enhancing the efficacy of cancer treatments.

Understanding the causal relationships between immune cell populations and cancer development remains a critical challenge in tumor immunology.

We employed Mendelian Randomization analysis leveraging genome-wide association studies of 612 immune cell traits and 91 cancer types to systematically evaluate causal associations. Single-cell RNA sequencing and computational deconvolution analyses were performed to characterize myeloid cell subpopulations in melanoma samples.

Our analysis revealed significant relationships between specific immune cell subsets and cancer risk, particularly highlighting the role of CD33 + myeloid cells in melanoma pathogenesis. Single-cell RNA sequencing identified distinct CD33high myeloid subpopulations characterized by elevated expression of complement cascade components and chemokine signaling pathways. Through computational deconvolution of The Cancer Genome Atlas melanoma cohort, we demonstrated that elevated CD33high monocyte abundance correlates with increased immune dysfunction scores, reduced CD8 + T cell infiltration, and poor survival outcomes.

Here we delineate the multifaceted mechanisms through which CD33 + myeloid cell populations orchestrate perturbations in the tumor-immune microenvironmental landscape, manifesting in compromised immunosurveillance and enhanced tumor progression. Our findings illuminate novel therapeutic opportunities through targeted modulation of myeloid cell function, while providing a systematic framework for understanding the complex interplay between immune cell populations and oncogenic processes.

HNSCC remains a substantial health issue, with treatment options including surgery, radiation, and platinum-based chemotherapy. Unfortunately, despite progress in research, only modest gains have been made in disease control, with existing treatments resulting in significant functional and quality-of-life issues. The introduction of immunotherapy in the treatment of HNSCC has resulted in some improvements in outlook for patients and is now standard of care for populations with both recurrent and metastatic disease. However, despite the early successes, responses to immune checkpoint inhibition (ICI) remain modest to low, approaching 14%-22% objective response rates. Challenges to the effectiveness of ICI and other immunotherapies are complex, including the diverse and dynamic molecular plasticity and heterogeneity of HNSCCs; lack of immunogenic antigens; accumulated suppressive immune populations such as myeloid cells and dysfunctional T cells; nutrient depletion; and metabolic dysregulation in the HNSCC tumor microenvironment. In this Review, we explore the mechanisms responsible for immunotherapy resistance, dissect these challenges, and discuss potential opportunities for overcoming hurdles to the development of successful immunotherapy for HNSCC.

In recent years, the utilization of nanocarriers has significantly broadened across a diverse spectrum of biomedical applications. However, the clinical translation of these tiny carriers is limited and encounters hurdles, particularly in the intricate landscape of the tumor microenvironment. Lung cancer poses unique hurdles for nanocarrier design. Multiple physiological barriers hinder the efficient drug delivery to the lungs, such as the complex anatomy of the lung, the presence of mucus, immune responses, and rapid clearance mechanisms. Overcoming these obstacles necessitates a targeted approach that minimizes off-target effects while effectively penetrating nanoparticles/cargo into specific lung tissues or cells. Furthermore, understanding the cellular uptake mechanisms of these nano carriers is also essential. This knowledge aids in developing nanocarriers that efficiently enter cells and transfer their payload for the most effective therapeutic outcome. Hence, a thorough understanding of biological cues becomes crucial in designing multifunctional nanocarriers tailored for treating lung cancer. This review explores the essential biological cues critical for developing a flexible nanocarrier specifically intended to treat lung cancer. Additionally, it discusses advancements in nanotheranostics in lung cancer.

Immune checkpoint inhibitors (ICIs) have improved outcomes of patients with many different cancers. These antibodies target molecules such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4) which normally function to limit immune activity. Treatment with ICIs reactivates T cells to destroy tumor cells in a highly specific manner, which in some patients, results in dramatic remissions and durable disease control. Over the last decade, much effort has been directed at characterizing factors that drive efficacy and resistance to ICI therapy. Food and Drug Administration (FDA)-approved biomarkers for ICI therapy have facilitated more judicious treatment of cancer patients and transformed the field of precision oncology. Yet, adaptive immunity against cancers is complex, and newer data have revealed the potential utility of other biomarkers. In this review, we discuss the utility of currently approved biomarkers and highlight how emerging biomarkers can further improve the identification of patients who benefit from ICIs.

Patients with advanced metastatic colorectal cancer (mCRC) typically exhibit significant interindividual differences in treatment responses and face poor survival outcomes. To systematically analyze the heterogeneous tumor progression and recurrence observed in advanced mCRC patients, we developed a quantitative cancer-immunity cycle (QCIC) model. The QCIC model employs differential equations to capture the biological mechanisms underlying the cancer-immunity cycle and predicts tumor evolution dynamics under various treatment strategies through stochastic computational methods. We introduce the treatment response index (TRI) to quantify disease progression in virtual clinical trials and the death probability function (DPF) to estimate overall survival. Additionally, we investigate the impact of predictive biomarkers on survival prognosis in advanced mCRC patients, identifying tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs) as key predictors of disease progression and the tumor-infiltrating CD4+ Th1/Treg ratio as a significant determinant of survival outcomes. This study presents an approach that bridges the gap between diverse clinical data sources and the generation of virtual patient cohorts, providing valuable insights into interindividual treatment variability and survival forecasting in mCRC patients.

Cancer is a leading cause of mortality and morbidity worldwide. Nanomaterials, unique optical, magnetic, and electrical properties at the nanoscale (1-100 nm), have been engineered to improve drug capacity, bioavailability, and specificity in cancer treatment. These advancements address toxicity and lack of selectivity in conventional therapies, enabling precise targeting of cancer cells, the tumour microenvironment, and the immune system. Among emerging approaches, bacterial treatment shows promise due to its natural ability to target cancer and its diverse therapeutic mechanisms, which nanotechnology can further enhance. Bacteria-based drug delivery systems leverage bacteria's adaptability and survival strategies within the human body. Bacterial derivatives, such as bacterial ghosts (BGs), bacterial extracellular vesicles (BEVs), and dietary toxins, are recognised as effective biological nanomaterials capable of carrying nanoparticles (NPs). These systems have attracted increasing attention for their potential in targeted NP delivery for cancer treatment. This study explores the use of various bacteria and their byproducts as NP delivery vehicles, highlighting their potential in treating different types of cancer. By combining the strengths of nanotechnology and bacterial therapy, these innovative approaches aim to revolutionise cancer treatment with improved precision and efficacy.

The tumor stroma consists mainly of extracellular matrix, fibroblasts, immune cells, and vasculature. Its structure and functions are altered during malignancy: tumor cells transform fibroblasts into cancer-associated fibroblasts, which exhibit immunosuppressive activities on which growth and metastasis depend. These include exclusion of immune cells from the tumor nest, cancer progression, and inhibition of T-cell-based immunotherapy. To understand these complex interactions, we measure the density of different cell types in the stroma using immunohistochemistry techniques on tumor samples from lung cancer patients. We incorporate these data into a minimal dynamical system, explore the variety of outcomes, and finally establish a spatio-temporal model that explains the cell distribution. We reproduce that cancer-associated fibroblasts act as a barrier to tumor expansion, but also reduce the efficiency of the immune response. Our conclusion is that the final outcome depends on the parameter values for each patient and leads to either tumor invasion, persistence, or eradication as a result of the interplay between cancer cell growth, T-cell cytotoxicity, and fibroblast activity. However, despite the existence of a wide range of scenarios, distinct trajectories, and patterns allow quantitative predictions that may help in the selection of new therapies and personalized protocols.

CD44, a widely recognized cancer stem cell marker, displayed a vital participation in the cancer immune invasion and may related with the response to the immunotherapy. However, the role of CD44 in cancer immunology is not well defined. Therefore, we intended to explore its prognostic value and potential immunological functions across 33 human cancer types.

Based on the data of patients from The Cancer Genome Atlas (TCGA), Sangerbox was used to analyze the correlations between CD44 expression and tumor-infiltrated immune cells, immune checkpoints, neoantigens, microsatellite instability (MSI), and tumor mutational burden (TMB) in human cancers. A mouse model xenografted with shRNA-CD44 MC38 was established.

The elevated CD44 was associated with tumor stage and prognosis in several different cancers. GSEA results showed that upregulated CD44 involved in cancer stem cell associated process, antigen processing and presentation, and immune cells proliferation and activation. CD44 plays an essential role in the tumor immune regulation and immune checkpoints inhibitor response. The correlation of CD44 gene expression and infiltration levels of immune cells varied across different cancer types. Notably, the upregulation of CD44 expression is positively correlated with regulatory CD4 T cells, macrophages M1 and M2 in several analyzed cancers. Furthermore, we verified the effect of CD44 on tumor growth and immune microenvironment in mouse xenografted with shRNA-CD44 MC38. Moreover, DNA methylation existed in CD44 expression and associated with dysfunctional T-cell phenotypes via different mechanisms, thus resulting in tissue-dependent prognoses.

CD44 is both a cancer stem cell marker and a potential prognostic and immunological biomarker in various malignant tumors. Moreover, CD44 could be a novel target for immune-based therapy.

High arginase activity is associated with several pathological conditions, including TGF-β-induced fibrosis, by increasing levels of the proline precursor l-ornithine, thereby promoting collagen biosynthesis and increasing oxidative stress due to nitric oxide synthase (NOS) uncoupling. The natural piceatannol has been shown to have beneficial effects on collagen deposition, fibrosis and oxidative stress. In this study, we present an in-depth structure-activity relationship study on arginase I, which resulted in the thioamide derivative 12a with dual catechol rings that displays potent inhibitory activity with IC₅₀ values of 9 μM and 55 μM for bovine and human arginase I, respectively. Quantum chemical modelling suggested that the sulphur atom in the thioamide group plays a crucial role in binding affinity by forming a stable hydrogen bond within the active site of the enzyme. In addition, compound 12a demonstrated high radical scavenging activity and effectively normalised collagen and procollagen levels at 5 μM in an in vitro cell model of a dermal fibrosis.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally. The tumor microenvironment (TME) plays a pivotal role in HCC progression, characterized by dynamic interactions between stromal components, immune cells, and tumor cells. Key immune players, including tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs), MDSCs, dendritic cells (DCs), and natural killer (NK) cells, contribute to immune evasion and tumor progression. Recent advances in immunotherapy, such as immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell therapy (ACT), and combination therapies, have shown promise in enhancing anti-tumor responses. Dual ICI combinations, ICIs with molecular targeted drugs, and integration with local treatments or radiotherapy have demonstrated improved outcomes in HCC patients. This review highlights the evolving understanding of the immune microenvironment and the therapeutic potential of immunotherapeutic strategies in HCC management.

Over the past few decades, cancer immunotherapy has experienced a significant revolution due to the advancements in immune checkpoint inhibitors (ICIs) and adoptive cell therapies (ACTs), along with their regulatory approvals. In recent times, there has been hope in the effectiveness of cancer vaccines for therapy as they have been able to stimulate de novo T-cell reactions against tumor antigens. These tumor antigens include both tumor-associated antigen (TAA) and tumor-specific antigen (TSA). Nevertheless, the constant quest to fully achieve these abilities persists. Therefore, this review offers a broad perspective on the existing status of cancer immunizations. Cancer vaccine design has been revolutionized due to the advancements made in antigen selection, the development of antigen delivery systems, and a deeper understanding of the strategic intricacies involved in effective antigen presentation. In addition, this review addresses the present condition of clinical tests and deliberates on their approaches, with a particular emphasis on the immunogenicity specific to tumors and the evaluation of effectiveness against tumors. Nevertheless, the ongoing clinical endeavors to create cancer vaccines have failed to produce remarkable clinical results as a result of substantial obstacles, such as the suppression of the tumor immune microenvironment, the identification of suitable candidates, the assessment of immune responses, and the acceleration of vaccine production. Hence, there are possibilities for the industry to overcome challenges and enhance patient results in the coming years. This can be achieved by recognizing the intricate nature of clinical issues and continuously working toward surpassing existing limitations.

Urological tumours are a type of neoplasms that significantly jeopardise human life and wellbeing. Cancer-associated fibroblasts (CAFs), serving as the primary component of the stromal cellular milieu, form a diverse cellular cohort that exerts substantial influence on tumourigenesis and tumour progression. In this review, we summarised the literatures regarding the functions of CAFs in the urinary tumour microenvironment (TME). We primarily examined the multifaceted activities of CAFs in the TME of urological system tumours, including inhibiting tumour immunity, remodelling the extracellular matrix, promoting tumour growth, metastasis, drug resistance and their clinical applications. We also discussed potential future directions for leveraging artificial intelligence in CAFs research. KEY POINTS: The interaction of CAFs with various cell secretory factors in the TME of urological tumors. The application of CAFs in diagnosis, treatment and prognosis of urological tumors.

Currently, cancer immunotherapy strategies are primarily formulated based on the patient's present condition, representing a "static" treatment approach. However, cancer progression is inherently "dynamic," as the immune environment is not fixed but undergoes continuous changes. This dynamism is characterized by the ongoing interactions between tumor cells and immune cells, which ultimately lead to alterations in the tumor immune microenvironment. This process can be effectively elucidated by the concept of cancer immunoediting, which divides tumor development into three phases: "elimination," "equilibrium," and "escape." Consequently, adjusting immunotherapy regimens based on these distinct phases may enhance patient survival and improve prognosis. Targeting ferroptosis is an emerging area in cancer immunotherapy, and our findings reveal that the antioxidant systems associated with ferroptosis possess dual roles, functioning differently across the three phases of cancer immunoediting. Therefore, this review delve into the dual role of the ferroptosis antioxidant system in tumor development and progression. It also propose immunotherapy strategies targeting ferroptosis at different stages, ultimately aiming to illuminate the significant implications of targeting ferroptosis at various phases for cancer immunotherapy.

Immunotherapy has transformed cancer treatment paradigms, but its effectiveness depends largely on the immunogenicity of the tumor. Unfortunately, the high resemblance of cancer to normal tissues makes most tumors immunologically 'cold', with a poor response to immunotherapy. Danger signals are critical for breaking immune tolerance and mobilizing robust, long-lasting antitumor immunity. Recent studies have identified inflammatory cell death modalities and their power in providing danger signals to trigger optimal tumor suppression. However, key mediators of inflammatory cell death are preferentially silenced during early tumor immunoediting. Strategies to rejuvenate inflammatory cell death hold great promise for broadening immunotherapy-responsive tumors. In this review, we examine how inflammatory cell death enhances tumor immunogenicity, how it is suppressed during immunoediting, and the potential of harnessing it for improved immunotherapy.

The combination of nivolumab and ipilimumab, which act on different immune checkpoint molecules, is a promising first-line treatment strategy for advanced nonsmall cell lung cancer (NSCLC). However, real-world clinical data on this regimen, particularly regarding the relationship between adverse events (AEs) and efficacy, are inadequate.

This real-world retrospective study was conducted on patients with advanced or recurrent NSCLC treated using a combination of nivolumab and ipilimumab as a first-line treatment. We extracted the data of consecutive eligible patients from four institutions in Japan between December 2020 and November 2022.

The study population comprised 184 patients who received nivolumab plus ipilimumab (median follow up period: 13.0 months [0.3-35.0]). In total, 81.0% (n = 149) of the patients were men, and the median age was 72.0 years (range: 46-80). The median progression-free survival (PFS) and overall survival (OS) were 6.6 months (95% confidence interval [CI]: 4.7-8.2) and 17.4 months (95% CI: 11.9-20.4), respectively. Skin disorders, liver dysfunction, thyroid dysfunction, and pneumonitis were the most common adverse events (AEs), with AEs occurring in 154 patients (83.7%). The median PFS in the AE group was longer than that in the non-AE group (8.2 vs. 2.6 months, p < 0.0001). The median OS in the AE group was also better than that in the non-AE group (19.3 vs. 6.1 months, p < 0.0001). Multivariate logistic regression analysis identified smoking history and high PD-L1 expression as factors related to the incidence of grade 3 and 4 AEs, respectively. The incidence of multiple AEs revealed a significant association with a longer PFS and OS. Skin disorders, adrenal insufficiency, and eosinophilia were the AEs with the greatest impact on survival.

Patients who experienced AEs had significantly longer PFS. Among AEs, the occurrence of skin disorders, adrenal insufficiency, and eosinophilia were likely to prolong PFS and OS.

The role of T cell immunity during antineoplastic therapy is poorly understood. In the BEGYN-1 study, patients with breast cancer underwent quarterly assessments prior to and during antineoplastic therapy over a period of 12 months.

We used flow cytometry and multiplex immunoassays to quantify 25 T cell subpopulations and seven T cell associated plasma cytokines in peripheral blood from 92 non-metastatic breast cancer patients, respectively. In addition, the association between T cell dynamics and the outcome of patients undergoing neoadjuvant chemotherapy was investigated.

In patients undergoing chemotherapy, a significant reduction in T helper (Th) cells, particularly naïve central and effector cells and thymus positive Th cells, was observed over time. Interestingly, Th1 immune response-associated cytokines (IL-12, TNF, IFN-γ) declined while Th2 cells and cytotoxic T cells increased over time.

We conclude that in breast cancer patients, chemotherapy is associated with a transition from a Th1 immune response towards Th2 and an increase in cytotoxic T cells, whereas in patients without chemotherapy, these alterations were less pronounced. Future studies should clarify whether patterns of T cell subsets or plasma cytokines can be used as biomarkers to monitor or even improve therapeutic interventions.

The process of tumor development involves tumor cells eluding detection and suppression of immune responses, which can cause decreased tumor cell antigenicity, expression of immunosuppressive molecules, and immunosuppressive cell recruitment to the tumor microenvironment (TME). Immunologically and genomically integrated analysis (immunogenomic analysis) of patient specimens has revealed that oncogenic aberrant signaling is involved in both carcinogenesis and immune evasion. In noninflamed cancers such as epidermal growth factor receptor (EGFR)-mutated lung cancers, genetic abnormalities in cancer cells contribute to the formation of an immunosuppressive TME by recruiting immunosuppressive cells, which cannot be fully explained by the cancer immunoediting hypothesis. This review summarizes the latest findings regarding the links between cancer genetic abnormalities and immunosuppression causing clinical resistance to immunotherapy. We propose the concepts of immunogenomic cancer evolution, in which cancer cell genomic evolution shapes the immunosuppressive TME, and immunogenomic precision medicine, in which cancer immunotherapy can be combined with molecularly targeted reagents that modulate the immunosuppressive TME.

Genome-wide plasma cfDNA pan-cancer screening of 1002 healthy elderly identified 15 individuals with CNAs of unknown origin. Nine participants were reassessed over 3-5 years through health questionnaires, WB-MRI, and cfDNA and blood analyses. CNAs resolved in two cases but persisted in seven mainly associated with low-grade clonal mosaicism. These findings suggest cfDNA CNAs may be transient or serve as early markers of clonal mosaicism, preceding clinical detection by years.

Given that natural killer (NK; CD3 - CD56 +) cells-mediated antibody-dependent cell cytotoxicity (ADCC) plays an important role in targeting neuroblastoma (NB) cells, adoptive cell therapy (ACT) utilizing expanded and activated haploidentical NK cells has emerged as a promising immunotherapeutic approach in pediatric patients with high-risk NB. In this pilot study, five pediatric patients with high-risk NB were enrolled. After harvesting hematopoietic progenitor cells (HPCs), patients received an intravenous infusion of high-activity iodine-131 (131I)-meta-iodobenzylguanidine (131I-MIBG). Seven days after the 131I-MIBG infusion and before the delivery of a single infusion of haploidentical purified NK cells, patients were administered a preparative regimen to establish a lymphodepleted host environment conducive to improved donor NK cell survival. Four days after the NK cell infusion, patients underwent the conditioning regimen, then received autologous hematopoietic stem cell transplantation (AHSCT). All patients achieved successful neutrophil and platelet engraftment. No adverse reactions were noted during or after the infusion of NK cells. Our study shows that incorporating NK cell infusion before AHSCT as a component of the conditioning regimen for consolidative therapy in pediatric patients with high-risk NB can be safe and well tolerated. IRCT Registration Number: IRCT20140818018842N32.