Adaptive immune resistance in cancer describes the various mechanisms by which tumors adapt to evade anti-tumor immune responses. IFN-γ induction of programmed death-ligand 1 (PD-L1) was the first defined and validated adaptive immune resistance mechanism. The endoplasmic reticulum (ER) is central to adaptive immune resistance as immune modulatory secreted and integral membrane proteins are dependent on ER. Sigma1 is a unique ligand-regulated integral membrane scaffolding protein enriched in the ER of cancer cells. PD-L1 is an integral membrane glycoprotein that is translated into the ER and processed through the cellular secretory pathway. At the cell surface, PD-L1 is an immune checkpoint molecule that binds PD-1 on activated T-cells and blocks anti-tumor immunity. PD-L1 can also be incorporated into cancer cell-derived extracellular vesicles (EVs), and EV-associated PD-L1 can inactivate T-cells within the tumor microenvironment. Here, we demonstrate that a selective small molecule inhibitor of Sigma1 can block IFN-γ mediated adaptive immune resistance in part by altering the incorporation of PD-L1 into cancer cell-derived EVs. Sigma1 inhibition blocked post-translational maturation of PD-L1 downstream of IFN-γ/STAT1 signaling. Subsequently, EVs released in response to IFN-γ stimulation were significantly less potent suppressors of T-cell activation. These results suggest that by reducing tumor derived immune suppressive EVs, Sigma1 inhibition may promote antitumor immunity. Sigma1 modulation presents a novel approach to regulating the tumor immune microenvironment by altering the content and production of EVs. Altogether, these data support the notion that Sigma1 may play a role in adaptive immune resistance in the tumor microenvironment.

Cancer cells evade immune responses by interacting with PD-1 and its ligand, PD-L1. Although monoclonal antibodies targeting this pathway have revolutionized oncology, their high production costs, poor oral bioavailability, and limited tumor penetration remain significant challenges. Small-molecule inhibitors provide a promising alternative, offering advantages such as improved tumor penetration and cost-effectiveness. This review highlights advancements in small-molecule PD-1/PD-L1 inhibitors, focusing on their mechanisms, structural designs, and therapeutic potential. Key innovations, including biphenyl scaffolds, heterocyclic frameworks, enhance binding efficiency and immune activation. The article effectively integrates fundamental principles of drug chemistry with real-world clinical needs, offering a comprehensive approach to the design of PD-1/PD-L1 small-molecule inhibitors. It systematically classifies various molecular structures, analyzes relevant industrial cases, and incorporates the most recent research findings. By examining these aspects, it uncovers the underlying logic driving the design process and provides a fresh, innovative perspective on advancing the field of immune small-molecule inhibitors for cancer therapy.

The abundant cell components of the adaptive immune system called T lymphocytes (T cells) play important roles in mediating immune responses to eliminate the invaders and create the memory of the germs to form a new immunity for the next encounter. Among them, cytotoxic T cells expressing cell-surface CD8 are the most critical effector cells that directly eradicate the target infected cells by recognizing antigens presented by major histocompatibility complex class I molecules to protect our body from pathological threats. In the continuous evolution of immunotherapy, various CD8+ T cell-based therapeutic strategies have been developed based on the role and molecular concept of CD8+ T cells. The emergence of such remarkable therapies provides promising hope for multiple human disease treatments such as autoimmunity, infectious disease, cancer, and other non-infectious diseases. In this review, we aim to discuss the current knowledge on the utilization of CD8+ T cell-based immunotherapy for the treatment of various diseases, the molecular basis involved, and its limitations. Additionally, we summarize the recent advances in the use of CD8+ T cell-based immunotherapy and provide a comprehensive overview of CD8+ T cells, including their structure, underlying mechanism of function, and markers associated with CD8+ T cell exhaustion. Building upon these foundations, we delineate the advancement of CD8+ T cell-based immunotherapies with fundamental operating principles followed by research studies, and challenges, as well as illustrate human diseases involved in this development.

RIP140 (receptor interacting protein of 140 kDa) is an important player in breast cancer (BC) by regulating key cellular pathways such as nuclear hormone receptor signaling. In order to identify additional genes specifically regulated by RIP140 in BC, we performed a transcriptomic analysis after silencing its expression in MCF-7 cells. We identified the interferon γ (IFNγ) signaling as being substantially repressed by RIP140 knockdown. Using the GBP1 (guanylate binding protein 1) gene as a reporter of IFNγ signaling, we demonstrated its robust induction by RIP140 through an ISRE motif, leading to a significant reduction of its induction upon IFNγ treatment. Furthermore, we showed that low levels of RIP140 amplified the IFNγ-dependent inhibition of BC cell proliferation. In line with these data, reanalysis of transcriptomic data obtained in human BC samples revealed that IFNγ levels were associated with good prognosis only for BC patients exhibiting tumors expressing low levels of RIP140, thus confirming its effect on the anti-tumor activity of IFNγ provided by our experimental data. Altogether, this study identifies RIP140 as a new regulator of IFNγ signaling in breast tumorigenesis.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by its lack of estrogen, progesterone, and HER2 receptors, leading to limited treatment options and poor prognosis. This review synthesizes current research on the tumor microenvironment (TME) and immune cell crosstalk in TNBC to identify emerging therapeutic opportunities. The TME in TNBC is a complex ecosystem comprising immune cells, fibroblasts, and extracellular matrix components, which significantly influence tumor growth and metastasis. Single-cell RNA sequencing reveals T-cell heterogeneity and identifies prognostic genes. Regulatory T cells (Tregs) play a key role in immunosuppression, with thymidine kinase-1 (TK1) identified as a potential therapeutic target. MUC1-C and CXCL9 modulate the TME, impacting T-cell depletion and macrophage differentiation. Spatial analysis highlights the importance of cell-to-cell interactions in predicting recurrence. Epithelial-mesenchymal transition (EMT) and thermogenesis also influence the TME, while epigenetic modifications, such as HDAC inhibition, can induce pyroptosis and enhance immune cell recruitment. Integrating genomic information with TME analysis is crucial for developing personalized treatments, considering racial disparities in immune infiltration. Emerging therapies targeting immune checkpoints, modulating Treg activity, and inducing pyroptosis hold promise for improving TNBC patient outcomes. Future research should focus on multi-omics data, spatial transcriptomics, and patient-derived models to refine therapeutic interventions.

With the morbidity of cancer currently on a perpetual rise, there is a critical need for new treatment options. Current therapeutic options, such as chemotherapy and radiotherapy, are frequently employed; however, the high rate of recurrence underscores the incomplete understanding of tumour growth, progression, and the intricacies of their microenvironments. In this study, we review the roles that galectin-1 (Gal1) plays in suppressing immune surveillance in the tumour microenvironment. Studies have shown that Gal1 changes the immune system parameters: suppressing T cell function, sensitising resting T lymphocytes to Fas/FasL, decreasing cell proliferation, reducing adhesion to extracellular matrix, inhibiting Th1 cytokines, increasing M2 phenotype macrophages, and promoting angiogenesis. Gal1 has garnered increasing attention as a potential therapeutic target due to its involvement in tumour progression and immune evasion. Given the limitations and toxic side effects associated with current treatment options, alternative strategies targeting Gal1 have been explored for their therapeutic potential. Approaches such as OTX008, anti-Gal1 monoclonal antibodies, and Gal1-targeted vaccines have demonstrated the ability to downregulate tumour progression by inhibiting Gal1 activity. These findings highlight the therapeutic promise of Gal1 not only as a novel target for cancer therapy but also as a potential prognostic biomarker, offering opportunities for the development of more effective and less toxic treatment strategies.

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. Simulation across the selected parameter space of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8 + killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.

B7 homolog 3 (B7-H3, also known as CD276) is a novel member of the B7 immune protein family. There is a marked difference in the expression and distribution of B7-H3 protein and mRNA between normal and tumor tissues, with widespread expression in tumor tissues and a close relationship with tumor progression. B7-H3 activates or inhibits tumor immune responses by binding to receptors on the surface of immune cells. Apart from participating in tumor immune activities, it has regulatory effects on non-immunological functions, such as tumor migration and invasion, angiogenesis, glycometabolism, and drug resistance. Thus, it has important biological functions in regulating the progression of malignant tumors. Current research on the structure, function, and therapeutic methods of B7-H3 is continuously breaking new ground, deepening our understanding of B7-H3, and promoting the development of therapeutic drugs targeting this new protein. This review briefly discusses the structure and distribution of B7-H3, as well as its immune and non-immune functions in the progression of cancer. It also summarizes the research progress on drugs targeting B7-H3 and the latest developments in clinical trials, highlighting their significant potential for the treatment of malignant tumors.

Colorectal cancer (CRC) is among the foremost causes of cancer-related mortality worldwide; however, individuals with microsatellite-stable (MSS) disease-who constitute most CRC diagnoses-derive limited benefit from existing immunotherapeutic approaches. Here, we outline emerging methods designed to address the inherent resistance of MSS CRC to immune checkpoint inhibitors (ICIs). Recent findings emphasize how the immunosuppressive tumor microenvironment (TME) in MSS CRC, marked by diminished immunogenicity and high levels of regulatory T cells and myeloid-derived suppressor cells, restricts effective antitumor immune activity. Combination regimens that merge ICIs with chemotherapy, anti-angiogenic agents, or targeted blockade of pathways such as TGF-β and VEGF have shown encouraging early outcomes, including enhanced antigen presentation and T-cell penetration. Novel immunomodulatory platforms-such as epigenetic modifiers, oncolytic viruses, and engineered probiotic vaccines-are under assessment to further reprogram the TME and boost therapeutic efficacy. Concurrently, progress in adoptive cell therapies (for example, chimeric antigen receptor (CAR) T cells) and the development of cancer vaccines targeting tumor-associated and neoantigens promise to extend immune control over MSS CRC. In parallel, improving patient selection through predictive biomarkers-from circulating tumor DNA (ctDNA) to gene expression signatures and specific molecular subtypes-could refine individualized treatment strategies. Finally, interventions that alter the gut microbiome, including probiotics and fecal transplantation, serve as complementary tools to strengthen ICI responses. Taken together, these insights and combined treatment strategies lay the foundation for more successful immunotherapeutic interventions in MSS CRC, ultimately aiming to provide sustained clinical benefits to a broader spectrum of patients.

The breast cancer (BC)-related mortality is higher and the immunity is altered in women living with HIV (WLWH) compared to HIV-negative women. Therefore, tumor samples of 296 black BC patients from South Africa and Namibia with known age, HIV status, tumor stage, hormone receptor and HER2 status and overall survival (OS) are analyzed for components of the tumor microenvironment (TME). WLWH (n = 117), either with suppressed viral activity (HR = 1.25) or with immune suppression (HR = 2.04), have a shorter OS. HIV status is associated with increased numbers of CD8+ T cells in the TME compared to HIV-negative patients; no correlation is found with CD4+ T cell numbers in the blood. Moreover, an increased expression of CD276/B7-H3 and a more pronounced IFN-γ signaling in the tumors are found in WLWH, independent of age, stage, and BC subtypes. In conclusion, altered T cell composition and CD276 expression in WLWH may contribute to inferior survival and can be used for targeted treatment.

Bacterial outer membrane vesicles (OMVs) represent powerful immunoadjuvant nanocarriers with the capacity to reprogram the tumor microenvironment (TME) and activate immune responses. Here, we investigate a nanotherapeutic platform integrating immunostimulatory cytosine-phosphate-guanine oligodeoxynucleotides (CpG-ODNs, hereafter termed CpG) into mesoporous silica nanoparticles cloaked with OMVs (CpG@MSN-PEG/PEI@OMVs) for cancer immunotherapy. Systemic administration of these nanohybrids facilitates precise tumor targeting, induces antitumor cytokines such as IFNγ, and suppresses immunosuppressive cytokine TGF-β, reshaping the TME. Additionally, CpG@MSN-PEG/PEI@OMVs promote M1 macrophage polarization, dendritic cell maturation, and the generation of durable tumor-specific immune memory, resulting in pronounced tumor regression with minimal systemic toxicity. The platform demonstrates efficacy against metastatic and solid tumor models including 4T1 breast and MC38 colorectal cancers. Transcriptomic analyses reveal that CpG@MSN-PEG/PEI@OMVs enhance mitochondrial oxidative phosphorylation in T cells within tumor-draining lymph nodes, mitigating T cell exhaustion and restoring metabolic fitness. These results support the potential of CpG@MSN-PEG/PEI@OMVs as a modular nanoplatform to modulate innate and adaptive immunity in cancer immunotherapy.

Cancer cell survival and proliferation are correlated with increased metabolic activity and consequent oxidative stress, driving metabolic shifts that interfere with the immune response to malignant cells. This is the case of high-energy-demanding angioimmunoblastic T cell lymphoma (AITL), a highly aggressive cancer with poor survival rates, where malignant CD4+ PD-1high T cells show increased mitochondrial activity and Reactive oxygen species (ROS) accumulation. Here, we report that administration of ROS scavenging cerium oxide (CeO2) nanoparticles in an AITL preclinical mouse model leads to their preferential accumulation in the spleen, where the CD4+ PD-1high T cells driving malignancy were significantly reduced. This was accompanied by activation of previously exhausted cytotoxic CD8+ T cells, restoring their potent antitumor function. As a result, survival rates dramatically increase with no observed toxicity to healthy cells or tissues. Overall, it highlights the correlation between increased energy demand, increased mitochondrial mass, increased PD-1 expression, increased ROS production, and immune suppression and how this vicious loop can be stopped by scavenging ROS.

Kujigamberol, a dinorlabdane compound isolated from Kuji amber, exerts multiple biological effects, including anti-allergic and anti-inflammatory activities. The present study demonstrated that kujigamberol inhibited cytokine production by T cells. In response to a phorbol 12-myristate 13-acetate (PMA) and ionomycin (IM) stimulation, kujigamberol suppressed interferon-γ (IFN-γ) and interleukin-2 (IL-2) mRNA expression in murine T-cell lymphoma BW5147 cells stably transfected with the T-box transcription factor eomesodermin. IL-4 and Fas ligand mRNA expression was also inhibited by kujigamberol. In the murine cytotoxic T-cell line CTLL-2, kujigamberol more strongly decreased IFN-γ mRNA expression induced by IM alone than that induced by the combination of PMA and IM. A luciferase reporter assay showed that kujigamberol preferentially reduced nuclear factor of activated T cell (NFAT)-dependent transcription in human embryonic kidney 293T cells. Unlike the calcineurin inhibitor FK506, kujigamberol did not markedly affect NFATc2 protein levels in BW5147 cells but interfered with the binding of NFATc2 to the IFN-γ and IL-2 promoters. These results indicate that kujigamberol inhibited IFN-γ and IL-2 mRNA expression by preventing the binding of NFATc2 to their promoters; therefore, it has potential as an immunosuppressive agent.

Hepatocellular Carcinoma (HCC) is related to dysregulated lipid metabolism and immunosuppressive microenvironment. This study developed a genetic risk model using lipid metabolism-related genes to predict survival and immune patterns in HCC patients.

Differentially expressed genes (DEGs) related to lipid metabolism were identified in HCC via the TCGA-LIHC dataset. A risk model for survival prediction was constructed via DEGs related to survival. The immune signature associated with the risk model was also evaluated by the CIBERSORT algorithm, tumor immune dysfunction and exclusion algorithm, and single sample gene set enrichment analysis.

This study identified six lipid metabolism-related genes, ADH4, LCAT, CYP2C9, CYP17A1, LPCAT1, and ACACA, to construct a lipid metabolism-related gene risk model that can divide HCC patients into low- and high-risk groups. Internal and external validation verified that the risk model could be a signature that could effectively predict HCC patient prognosis. High-risk patients showed disrupted immune cell profiles, reduced tumor-killing capacity, and increased expression of immune checkpoint genes. However, they responded more favorably to immune checkpoint inhibitor (ICB) therapy. The top ten hub genes related to the risk model were associated with tumor progression and deteriorating prognosis. In vitro experiments verified that the downregulation of the top 1 hub gene CDK1 was correlated to the HCC cell proliferation.

The risk model constructed using lipid metabolism-related genes could effectively predict prognosis and was related to the immunosuppressive microenvironment and ICB immunotherapy. The hub genes related to the risk model were potential therapeutic targets.

T cell immune responses are triggered by antigenic peptides presented through major histocompatibility complex class Is (pMHC-Is), which play an important role in the genesis, development, and therapy of tumors. The capacity of a specific pMHC-I to elicit T cell responses is deeply influenced by its expression level (quantity) and its immunogenicity (quality). Tumor cells can evade T cell immunity by down-regulating the quantity of pMHC-Is or selectively eliminating highly immunogenic antigenic peptides. Augmenting the quantity or quality of pMHC-Is is essential for tumor immunotherapy. However, the complexity of pMHC-I regulation and tumor heterogeneity pose challenges to clinical strategies. Consequently, developing approaches grounded in comprehensive analyses of pMHC-I regulatory mechanisms remains a focal point in the research of T cell immunity. In this review, we discuss how tumors modulate their surface pMHC-Is through genetic, epigenetic, and proteomic mechanisms and summarize potential therapeutic strategies targeting these mechanisms, which may provide a valuable reference for the development of novel tumor immunotherapies based on pMHC-I modulation. Tumor cells can achieve immune escape by interfering with the quantity and quality of pMHC-Is, and corresponding immunotherapy can also be achieved by the regulation of pMHC-Is.

Immune checkpoint inhibitors (ICIs) are shown to improve cancer treatment effectiveness by boosting the immune system of the patient. Nevertheless, the unique and highly suppressive TME poses a significant challenge, causing heterogeneity of response or resistance in a considerable number of patients. This review focuses on the evasive attributes of the TME. Immune evasion mechanism in TME include immunosuppressive cells, cytokine and chemokine signaling, metabolic alterations and overexpression of immune checkpoint molecules such as PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA and their interactions within the TME. In addition, this review focuses on the overcoming resistance by targeting immunosuppressive cells, normalizing tumor blood vessels, blocking two or three checkpoints simultaneously, combining vaccines, oncolytic viruses and metabolic inhibitors with ICIs or other therapies. This review also focuses on the necessity of finding predictive markers for the stratification of patients and to check response of ICIs treatment. It remains to be made certain by new research and intelligent innovations how these discoveries of the TME and its interplay facilitate ICI treatment and change the face of cancer treatment.

Origanum vulgare ssp. hirtum is an aromatic plant native to various Mediterranean regions and has been traditionally used in folk medicine. This study investigates the chemical composition and the potential antitumor activity of its essential oil in a preclinical model of CT26 colorectal cancer in BALB/c mice. Mice received prophylactic oral administration of the essential oil, and tumor progression, immune modulation, and apoptosis were evaluated. Even treatment with low doses (350 parts per million, ppm in 100 μL final volume) of the essential oil significantly suppressed tumor growth by approximately 44%. This effect correlated with the enhanced expression of antitumorigenic cytokines, including a 2.7-fold increase in type I interferons (IFN), IFN-γ (from 46.5 to 111.9 pg/μL per mg of protein) and tumor necrosis factor alpha (TNF-α) (from 34.5 to 103 pg/μL per mg of protein). Furthermore, the production of granzyme B, a key mediator of cytotoxic immune cell function, was notably increased from 96.1 to 319.6 pg/μL per mg of protein. An elevated activation of caspase 3, a central effector caspase of all apoptotic cascades, was also observed in tumors from oregano-treated mice. These findings suggest that O. vulgare ssp. hirtum essential oil exhibits promising antitumor properties through immune modulation and immunity-mediated apoptosis induction, supporting its potential development as a bioactive compound for cancer prevention or therapy.

Bojungikki-tang (BJIKT), a traditional herbal formula with immunomodulatory properties, has synergistic effects with immune checkpoint inhibitors. However, the detailed molecular mechanisms underlying its effects on various immune cell types remain largely unexplored. Therefore, in this study, we aimed to propose a framework for understanding how herbal medicine modulates immunity through a systematic analysis of the drug-induced transcriptome and immune cell interaction networks. We obtained large-scale RNA-seq data for distinct five immune cell types (T cells, natural killer cells, B cells, macrophages, and dendritic cells) treated with BJIKT and its four major constituent herbs, totaling 180 sequenced samples. Transcriptomic analysis indicated that BJIKT significantly upregulated interferon-γ, TNF-α, and inflammatory pathways in B cells, macrophages, and dendritic cells. Although BJIKT did not directly activate T cells, it indirectly modulated their function through immune cell-cell interactions. The reconstructed network and cytokine assays identified IL-1β, IL-6, IL-8, MIP-1β, CXCL9, CXCL10, and TNF-α as critical cytokines influenced by BJIKT, playing pivotal roles in activating and recruiting various immune cells. Our findings provide insights into the immunomodulatory mechanisms of BJIKT and the unique actions of its constituent herbs. We highlight the potential for combining traditional herbal medicine with omics technologies to explore the therapeutic mechanisms of natural products as complementary therapies for advancing cancer immunotherapy.

Sjögren's disease (SjD) is a systemic autoimmune disorder primarily causing dry eyes and mouth. It frequently overlaps with other autoimmune diseases (AIDs), including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the genetic basis of SjD remains underexplored, limiting our understanding of its connections to other immune-mediated conditions. In this study, we aimed to identify gene networks associated with SjD through the integration of genetic, transcriptomic, and epigenomic data. We further compared the genetic factors of SjD with other immune-mediated diseases. We analyzed genome-wide association studies (GWAS) summary statistics, DNA methylation, and transcriptomic data using our in-house network-based methods, dmGWAS and EW_dmGWAS, to identify key gene modules associated with SjD. In dmGWAS analysis, discovery and evaluation datasets were used to identify consensus results. We conducted gene-set, cell-type, and disease-enrichment analyses on significant gene modules and explored potential drug targets. Genetic correlations and Mendelian randomization were applied to assess SjD's link with 17 other AIDs and 16 cancer types. dmGWAS identified 207 and 211 gene modules in the discovery and evaluation phases, respectively, while EW_dmGWAS detected 886 modules. Key modules highlighted 55 genes (discovery), 52 genes (evaluation), and 59 genes (EW_dmGWAS), with at least 50 genes from each analysis linked to AIDs and cancer. Enrichment analyses confirmed their relevance to immune and oncogenic pathways. We pinpointed four candidate drug targets associated with AIDs. We developed a novel integrative omics approach to identify potential genetic markers of SjD and compared them with AIDs and cancers. Our approach can be similarly applied to other disease studies.

Immunotherapy alone or in combination with chemotherapy or radiotherapy is the frontline treatment for melanoma and lung cancer. However, its role in prostate cancer is usually as a fourth-line treatment. It is usually employed in patients with metastasis, after androgen blockade and chemotherapy. This article reviews the immunosuppressive effects of prostate cancer and possible uses of various types of immunotherapies. It also considers when would be the optimal time to employ this type of therapy.

This study aimed to identify the cytokine expression profile in prostate cancer (PCa) patients compared to healthy individuals. Plasma samples from 75 PCa patients and 14 healthy controls were analyzed using Multiplex ELISA (Luminex) to measure the expression levels of 12 cytokines: IL-4, IL-5, IL-6, IL-10, IL-1β, IL-17A, IL-12p70, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, TNF-α, and IFN-γ. Differences in cytokine expression levels were analyzed using the Mann-Whitney test, Wilcoxon's rank-sum test, Spearman's rank correlation, and K-means Clustering unsupervised machine learning to validate cytokine expression patterns. In PCa patients, MIP-1α/CCL3, MIP-1β/CCL4, IFN-γ, and interleukins exhibited significantly higher expression levels; conversely, TNF-α and MCP-1/CCL2 both had decreased expression compared to healthy individuals. The clustering analysis confirmed that PCa patients exclusively exhibit the highest associations with MIP-1α/CCL3, IFN- γ, IL-12p70, IL-4, and IL-5. Furthermore, specific correlations between IL-4 and MIP-1 beta, IL-4 and IFN-gamma, IL-5 and IL-12p70, and IL-5 and IFN-gamma in PCa patients did not occur in healthy individuals. Such results will guide forthcoming in vitro and in vivo human prostate cancer-drug treatment models, paving the way for exploration of future drug targets and candidates with potential to predict FDA-approved prostate cancer treatment responses by targeting cytokine levels and the oncogenesis pathways.

Dysregulated cell movement is a hallmark of cancer progression and metastasis, the leading cause of cancer-related mortality. The metastatic cascade involves tumour cell migration, invasion, intravasation, dissemination, and colonisation of distant organs. These processes are influenced by reciprocal interactions between cancer cells and the tumour microenvironment (TME), including immune cells, stromal components, and extracellular matrix proteins. The epithelial-mesenchymal transition (EMT) plays a crucial role in providing cancer cells with invasive and stem-like properties, promoting dissemination and resistance to apoptosis. Conversely, the mesenchymal-epithelial transition (MET) facilitates metastatic colonisation and tumour re-initiation. Immune cells within the TME contribute to either anti-tumour response or immune evasion. These cells secrete cytokines, chemokines, and growth factors that shape the immune landscape and influence responses to immunotherapy. Notably, immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often dictated by the immune composition of the tumour site. Elucidating the molecular cross-talk between immune and cancer cells, identifying predictive biomarkers for ICB response, and developing strategies to convert cold tumours into immune-active environments is critical to overcoming resistance to immunotherapy and improving patient survival.

Immune checkpoint inhibitors (ICIs) targeting programmed death ligand-1 (PD-L1) provide clinical benefits for various advanced malignancies. However, the predictive factors that determine sensitivity to ICIs have not been fully elucidated. We focused on tumor-derived CXCL10/11 as a pivotal factor that determines the response to PD-L1 blockade by regulating T cell accumulation and tumor angiogenesis. We previously reported that CXCL10/11 was upregulated by interferon (IFN)-γ in ICI-sensitive tumor cells but not in ICI-resistant cells, including mouse Lewis lung carcinoma (LLC). In the present study, gene silencing of tumor-derived CXCL10/11 induced resistance to PD-L1 blockade in AB1-HA mesothelioma cell-bearing mice. To identify the mechanisms underlying ICI resistance, we performed a microarray analysis to compare the IFN-γ-inducible genes between ICI-sensitive AB1-HA and ICI-resistant LLC in vitro. A pathway analysis based on microarray data indicated that hypoxia-inducible factor (HIF) 1A is the key signal that inhibits CXCL10/11 expression. We revealed that the HIF1A inhibitors echinomycin (EC) and YC-1 upregulated CXCL10/11 genes induced by IFN-γ in tumor cells in vitro. In addition, combination therapy with PD-L1 blockade and EC demonstrated synergistic antitumor effects in LLC-bearing mice. Combination therapy enhanced tumor infiltration of CD8 T cells and suppressed tumor angiogenesis. The present study suggests that HIF1A signaling in tumor cells dominates ICI resistance via the downregulation of tumor-derived CXCL10/11.

As essential immune system regulators, cytokines are essential for modulating both innate and adaptive immunological responses. They have become important tools in cancer immunotherapy, improving the immune system's capacity to identify and destroy tumor cells. This article examines the background, workings, and therapeutic uses of cytokines, such as interleukins, interferons, and granulocyte-macropHage colony-stimulating factors, in the management of cancer. It examines the many ways that cytokines affect immune cell activation, signaling pathways, tumor development, metastasis, and prognosis by modifying the tumor microenvironment. Despite the limited effectiveness of cytokine-based monotherapy, recent developments have concentrated on new fusion molecules such as immunocytokines, cytokine delivery improvements, and combination techniques to maximize treatment efficacy while reducing adverse effects. Current FDA-approved cytokine therapeutics and clinical trial results are also included in this study, which offers insights into how cytokines might be used with other therapies including checkpoint inhibitors, chemotherapy, and radiation therapy to address cancer treatment obstacles. This study addresses the intricacies of cytokine interactions in the tumor microenvironment, highlighting the possibility for innovative treatment methods and suggesting fresh techniques for enhancing cytokine-based immunotherapies. PEGylation, viral vector-mediated cytokine gene transfer, antibody-cytokine fusion proteins (immunocytokines), and other innovative cytokine delivery techniques are among the novelties of this work, which focuses on the most recent developments in cytokine-based immunotherapy. Additionally, the study offers a thorough examination of the little-reviewed topic of cytokine usage in conjunction with other treatment techniques. It also discusses the most recent clinical studies and FDA-approved therapies, providing a modern perspective on the developing field of cancer immunotherapy and suggesting creative ways to improve treatment effectiveness while lowering toxicity. BACKGROUND: Cytokines are crucial in cancer immunotherapy for regulating immune responses and modifying the tumor microenvironment (TME). However, challenges with efficacy and safety have driven research into advanced delivery methods and combination therapies to enhance their therapeutic potential.

Bipolar disorder (BD) and major depressive disorder (MDD) are mood disorders. The most frequent clinical presentation of BD and MDD is depression, which contributes to high rates of misdiagnosis between disorders. To support diagnostic discrimination and therapeutic stratification, we aim to perform a systematic review and meta-analysis evaluating peripheral protein inflammatory biomarkers between BD and MDD, with a focus on the depressive state.

We conducted a literature search on PubMed, PsycInfo and Embase with no year/language restrictions. Original studies including human participants with a BD or MDD diagnosis which directly compared levels of peripheral protein inflammatory biomarkers between groups were included. A random effects meta-analysis was performed.

35 studies were included in the systematic review. 9 studies were included in the meta-analysis. The meta-analysis showed IL-7 (p < 0.01) levels were significantly decreased in BD, and IL-9 (p < 0.01), CCL3 (p = 0.03), CCL4 (p = 0.01), CCL5 (p = 0.02) and CCL11 (p = 0.04) levels were significantly increased in BD.

High heterogeneity and limited dataset size restricted our meta-analysis to a small subset of biomarkers and limited our exploration of the effects of moderator variables.

This study found differences in IL-7, IL-9, CCL3, CCL4, CCL5 and CCL11 between BD and MDD in a depressive state. These findings support the notion that inflammation is associated with mood disorder pathophysiology, particularly with respect to T-cell network dysregulation. Further studies can assist in better understanding differences between disorders and work towards clinical applications.

Suppression of tumor-reactive CD8+ T cells is common within the tumor microenvironment. However, little is known about how tumors systemically affect the overall CD8+ T cell compartment. Here we demonstrate that peripheral blood CD8+ T cells from patients with lung cancer showed altered compositions particularly within CD45RA-CCR7- effector memory subpopulation. Specifically, patients with lung cancer exhibited increased frequency of more differentiated effector memory cells, which are less susceptible to T cell-receptor-induced proliferation. Further analysis using single-cell RNA sequencing revealed that these alterations were correlated with reduced quiescence and increased spontaneous activation at a systemic level, indicative of homeostatic dysregulation of the entire CD8+ T cell population. This phenomenon was found to be correlated with a poor clinical response to immune checkpoint inhibitor therapy across four independent cohorts, consisting of a total of 224 patients with lung cancer. These findings suggest that lung cancers continue to counteract potentially tumor-reactive CD8+ T cells by inducing homeostatic dysregulation of the entire CD8+ T cell compartment systematically.

Tumor angiogenesis is a critical biological hallmark of cancer, which involves multiple molecularly regulated signaling pathways, including the angiopoietin (ANGPT)-Tie2 and the vascular endothelial growth factor (VEGF) signaling pathways. Despite initial optimism, targeting tumor angiogenesis in the treatment of lung adenocarcinoma (LUAD) has been unsatisfactory. Currently, monotherapy with PD-1/PD-L1 inhibitors, or their combination with bevacizumab, is considered the standard therapeutic approach for LUAD. Recent studies have shown that immunotherapy suppresses tumor angiogenesis and facilitates vascular normalization. However, whether and how anti-PD-L1 therapy influences tumor vasculature remains unclear.

To investigate the impact of immunotherapy on the vasculature of LUAD, a mouse model of lung adenocarcinoma was established by subcutaneous implantation of Lewis lung carcinoma cells in vivo. The effects of different treatments on microvessel density and pericyte coverage were explored, and the expression of angiogenesis-related factors was analyzed. Furthermore, to explore the molecular mechanisms through which IFN-γ regulates tumor blood vessels during immunotherapy, we elucidated the specific mechanisms in vitro by means of techniques such as siRNA, ChIP, RT-qPCR, Western blot, and immunofluorescence. Finally, the effects of IFN-γ on the proliferation, migration, and angiogenic function of endothelial cells (ECs) were evaluated through CCK-8, Transwell, and HUVEC tube formation assays.

Employing a mouse model of LUAD, we demonstrated that PD-L1 blockade therapy inhibits tumor angiogenesis and normalizes vasculature in an IFN-γ-signaling-dependent manner. Notably, anti-PD-L1 therapy reduced Tie2 and ANGPT2 expression, and these effects were reversed by the JAK1/2 inhibitor. Mechanistically, we demonstrated that IFN-γ inhibited Tie2 and ANGPT2 expression in ECs, and suppressed ANGPT2 gene transcription through the AKT-FOXO1 signaling pathway. Interestingly, IFN-γ-mediated activation of STAT1 exerts negative regulation by directly binding to the promoter regions of the ANGPT2 and TEK genes. Functionally, IFN-γ limits the migration, proliferation, and tube formation of ECs.

In conclusion, our results revealed a novel mechanism wherein IFN-γ-mediated inhibition of ANGPT2-Tie2 facilitates vascular normalization during immunotherapy in LUAD, which performs an essential function in the antitumor efficacy of immunotherapy.

Marek's disease virus (MDV) causes Marek's disease (MD) in chickens, characterized by malignant lymphomas and immunosuppression. Sporadic MD outbreaks continue to occur even among vaccinated flocks in certain regions due to the increased virulence of the field strains. However, the mechanisms of tumorigenesis and immunosuppression caused by MDV remain to be fully elucidated. We previously reported that the mRNA expression of programmed cell death 1 (PD-1), an immune checkpoint molecule, was increased in tumor lesions caused by MDV, and its expression was positively correlated with the mRNA expression of Meq, an MDV-specific oncogene. In this study, we characterized PD-1-expressing T-cell subsets in the spleen and tissues of chickens that developed tumors to investigate the association between PD-1 expression and immunosuppression. Flow cytometric analysis revealed that the proportion of PD-1-expressing CD4+ T-cells, which are targets of MDV tumorigenesis, increased in the spleen and tumor tissues of chickens with MD. The proportion of PD-1+ CD4+ T-cells was higher in Meq-expressing cells than in those that were not. In the spleens of chickens with MD, the proportions of PD-1-expressing cells were increased in CD8+ and γδ T-cells, which play pivotal roles in defense against MD pathogenesis, relative to those of spleens from uninfected chickens. Moreover, the proportion of PD-1+ CD8+ T-cells expressing interferon (IFN)-γ did not increase in the spleen of chickens with MD. Additionally, no difference in the proportion of IFN-γ+ γδ T-cells expressing and not expressing PD-1 was observed in the spleens of chickens with MD, although the proportion of IFN-γ+ γδ T-cells expressing PD-1 in the spleens of uninfected chickens was higher. The function of PD-1-expressing CD8+ and γδ T-cells in chickens may be impaired after developing MD, which may cause MDV-induced immunosuppression.

The tumour microenvironment is composed of a complex cellular network involving cancer, stromal and immune cells in dynamic interactions. A large proportion of this network relies on direct physical interactions between cells, which may impact patient responses to clinical therapy. Doublets in scRNA-seq are usually excluded from analysis. However, they may represent directly interacting cells. To decipher the physical interaction landscape in relation to clinical prognosis, we inferred a physical cell-cell interaction (PCI) network from 'biological' doublets in a scRNA-seq dataset of approximately 18,000 cells, obtained from 7 treatment-naive ovarian cancer patients. Focusing on cancer-stromal PCIs, we uncovered molecular interaction networks and transcriptional landscapes that stratified patients in respect to their clinical responses to standard therapy. Good responders featured PCIs involving immune cells interacting with other cell types including cancer cells. Poor responders lacked immune cell interactions, but showed a high enrichment of cancer-stromal PCIs. To explore the molecular differences between cancer-stromal PCIs between responders and non-responders, we identified correlating gene signatures. We constructed ligand-receptor interaction networks and identified associated downstream pathways. The reconstruction of gene regulatory networks and trajectory analysis revealed distinct transcription factor (TF) clusters and gene modules that separated doublet cells by clinical outcomes. Our results indicate (i) that transcriptional changes resulting from PCIs predict the response of ovarian cancer patients to standard therapy, (ii) that immune reactivity of the host against the tumour enhances the efficacy of therapy, and (iii) that cancer-stromal cell interaction can have a dual effect either supporting or inhibiting therapy responses.

Interferon gamma (IFNγ) can amplify immune cell-mediated anti-tumor immunity, as well as directly kill cancer cells. Ginsenoside Rh2 (Rh2), a bioactive compound in traditional Chinese medicine, exhibits anti-cancer effects such as inhibiting proliferation and metastasis. Our earlier research found that Rh2 combined with IFNγ enhanced CXCL10 secretion in cancer cells. Here, we explored whether Rh2 and IFNγ exerted more potent anti-cancer activity in vitro and in vivo, along with its mechanisms and clinical value. Our data showed that Rh2 in combination with IFNγ resulted in a remarkably increased cytotoxicity in colorectal cancer cells including HT29, LoVo and T84 cell lines. Consistently, intratumoral injection with Rh2 plus IFNγ further restricted the HT29 tumor growth in vivo, and importantly, it was demonstrated to be safe for mice. Meanwhile, the combo treatment activated the stimulator of interferon genes (STING) pathway in cancer cells, promoting the transcription of downstream type I interferon. RNA sequencing revealed a dramatically transcriptional alteration in cancer cells with combo treatment and indicated that Rh2 further augmented the activation of interferon signaling pathway, compared with the IFNγ alone. Inhibition of janus kinase (JAK) by ruxolitinib could significantly rescue the cell death-triggered by the combo treatment. Then, a gene set named Rh2+IFNγ signature genes (RISG) was defined, which contained top 20 significantly upregulated genes from the combo treatment. Patients who exhibited a favorable response to the immunotherapy had a higher expression of RISG in tumor compared with those who did not respond. And the high expression of RISG was correlated with better clinical outcome in patients with colorectal cancer (CRC) and skin cutaneous melanoma (SKCM). Herein, the combination of Rh2 with IFNγ served as a promising strategy for cancer treatment, and its-derived RISG gene set also exhibited potential value in predicting clinical outcome. Schematic diagram of the anti-cancer effect of Rh2 combined with IFNγ. The schematic diagram illustrated that ginsenoside Rh2 in combination with IFNγ robustly activated the interferon signals in cancer cells, ultimately leading a significant cell death of cancer cells. ISGs, interferon-stimulated genes. Created with BioRender.com.

Colorectal cancer (CRC) development is influenced by both iron and gut microbiota composition. While iron supplementation is routinely used to manage anemia in CRC patients, it may also impact gut microbiota and promote tumorigenesis. In this study, we investigated the impact of initial gut microbiota composition on iron-promoted tumorigenesis. We performed fecal microbiota transplantation (FMT) in ApcMin/+ mice using samples from healthy controls, CRC patients, and mice, followed by exposure to iron sufficient or iron excess diets.

We found that iron supplementation promoted CRC and resulted in distinct gut microbiota changes in ApcMin/+ mice receiving FMT from CRC patients (FMT-CRC), but not from healthy controls or mice. Oral treatment with identified bacterial strains, namely Faecalibaculum rodentium, Holdemanella biformis, Bifidobacterium pseudolongum, and Alistipes inops, protected FMT-CRC mice against iron-promoted tumorigenesis.

Our findings suggest that microbiota-targeted interventions may mitigate tumorigenic effects of iron supplementation in anemic patients with CRC.

Gastric cancer remains a significant global health burden with limited treatment options and high mortality. Syndecan-binding protein (SDCBP), a scaffolding protein involved in tumor differentiation, has attracted attention as a potential therapeutic target in cancers. However, its precise role in gastric cancer progression is not fully understood. In this study, through bioinformatics analysis and gastric cancer samples detection, we discovered that SDCBP was highly expressed in gastric cancer tissues, which was correlated with clinicopathological features such as tumor invasion depth and distant metastasis, and exhibited heterogeneity across histological or molecular subtypes. Elevated SDCBP expression promoted the proliferation, invasion and migration of gastric cancer cells, and modulated epithelial-mesenchymal transition (EMT) via the ERK signaling pathway. Xenograft experiments in mice confirmed that inhibiting SDCBP or ERK signaling could delay cancer progression. We also found that gastric cancer cells with SDCBP knockdown were able to inhibit the M2 polarization of cocultured macrophages, reduce chemotaxis and enhance phagocytosis of macrophages. Therefore, SDCBP plays a crucial role in driving gastric cancer progression. Targeting SDCBP in gastric cancer can partially reverse the malignant phenotype, and SDCBP is expected to be a promising therapeutic target for gastric cancer.

This study introduces TG-ME, an innovative computational framework that integrates transformer with graph variational autoencoder (GraphVAE) models for dissection of tumoral niches using spatial transcriptomics data and morphological images. TG-ME effectively identifies and characterizes niches in bench datasets and a high resolution NSCLC dataset. The pipeline consists in different stages that include normalization, spatial information integration, morphological feature extraction, gene expression quantification, single cell expression characterization, and tumor niche characterization. For this, TG-ME leverages advanced deep learning techniques that achieve robust clustering and profiling of niches across cancer stages. TG-ME can potentially provide insights into the spatial organization of tumor microenvironments (TME), highlighting specific niche compositions and their molecular changes along cancer progression. TG-ME is a promising tool for guiding personalized treatment strategies by uncovering microenvironmental signatures associated with disease prognosis and therapeutic outcomes.

A theranostic nanomedicine for CD3+ bispecific antibodies targeting glycoprotein-100 (GP-100) was tested in vivo using two radiation sessions. CT-imageable nanoparticles composed of hyaluronate-alginate and designed to release their contents upon radiation exposure were evaluated in a mouse model of B16-melanoma model in the left hind leg with pulmonary metastases.

In session 1, IFN-γ was encapsulated during the Fe polymerization of hyaluronate-alginate nanoparticles. Nine hours after the intravenous injection of 1 × 1010 IFN-γ nanoparticles, enough to observe dose escalation of either 10 or 20 Gy was administered using 140 keV-X-ray to the primary and metastatic tumors. In session 2, tebentafusp was encapsulated using the same method as in session 1. Seventy-two hours after the intravenous injection of 1 × 1010 tebentafusp-loaded nanoparticles, radiation was administered under conditions identical to those in session 1.

In session 1, IFN-γ-loaded nanoparticles selectively accumulated in the primary tumor and pulmonary metastasis by passing through the coarse endothelium of tumor vasculature, which could be visualized using CT. IFN-γ nanoparticles continuously released IFN-γ, facilitating the formation of the HLA-A*02:01-GP100-complex. In session 2, the tebentafusp-loaded nanoparticles continuously released tebentafusp, leading to the formation of an immunological synapse consisting of HLA-A*02:01-GP100, tebentafusp, and CD3 on T cells. CD3+ T cells release perforin and granzymes, resulting in the cytolysis of the primary tumor and pulmonary metastasis. This effect was synergistic with that of radiation, resulting in Enhancement Factor (EF) more than 1.

Theranostic nanomedicine demonstrated potential as a dual therapeutic and diagnostic strategy for targeting tumors and metastases, with synergistic effects observed when combined with radiation.

Opportunistic intramacrophagic infections are well-characterized in adult-onset immunodeficiency associated with neutralizing anti-IFN-γ autoantibodies (nAIGA).

Concomitant autoimmune and neoplastic diseases are rarely described.

This study included 50 patients diagnosed with adult-onset immunodeficiency due to nAIGA between 2014-2024. Thirty-three were retrospectively included before January 2022, and 17 out of 295 screened patients were enrolled prospectively since January 2022. Ten patients were excluded due to missing records. All patients had regular follow-ups; anti-IFN-γ titers, autoimmune markers and cancer survey were conducted according to the primary physician's evaluation.

The median age at diagnosis of adult-onset immunodeficiency was 57 years, and 53% were men. Malignancy occurred in 25%; genitourinary cancer predominated (n=4). Most (93%) patients had at least one positive autoimmune marker. Fifty-eight percent of patients were diagnosed with concomitant autoimmune diseases, and women (65%) predominated. Anti-nuclear antibody was positive in 61%, lupus anticoagulant in 50%, whilst autoimmune thyroiditis markers in 43%. Twenty-two percent of patients required long-term immunomodulation including biologic agents such as rituximab and daratumumab. Three patients (8%) died after a median interval of 9.4 years due to sepsis (n=2) and aggressive urothelial cancer (n=1). Most patients had decreasing nAIGA titers over time; two outliers with persistently high neutralizing antibodies developed late-onset malignancies.

Adult-onset immunodeficiency due to nAIGA is a syndrome associated with concomitant autoimmunity. Chronic infection and autoimmune-mediated inflammation may foster neoplastic changes, but the underlying mechanism is still undetermined. Autoimmune disease and cancer surveillance for patients with nAIGA is advised.

Colorectal cancer (CRC) remains a challenge for current immunotherapies. Vδ1+ γδ T cells offer a promising alternative because of their HLA-I-independent cytotoxicity and natural tissue tropism. We developed Delta One T (DOT) cells, a Vδ1+ γδ T cell-based adoptive cell therapy clinically explored for hematological malignancies but not yet for solid tumors. Here we demonstrate the capacity of DOT cells to target CRC cell lines and patient-derived specimens and organoids in vitro and to control tumor growth in an orthotopic xenograft model of CRC. Notwithstanding, we found tumor-infiltrating DOT cells to exhibit a dysregulated balance of cytotoxic and inhibitory receptors that paralleled that of endogenous Vδ1+ tumor-infiltrating lymphocytes and limited their cytotoxicity. To maximize efficacy, we unveil two strategies, increasing targeting through upregulation of NKG2D ligands upon butyrate administration and blocking the checkpoints TIGIT and PD1, which synergistically unleashed DOT cell cytotoxicity. These findings support DOT cell-based combinatorial approaches for CRC treatment.