Messenger RNA (mRNA) vaccines represent a versatile and scalable platform for cancer immunotherapy; however, their clinical efficacy depends critically on precise vaccine design capable of eliciting robust, selective, and durable antitumor immune responses. Recent advances in bioinformatics and artificial intelligence (AI) have substantially improved the rational design, evaluation, and optimization of mRNA-based cancer vaccines. In particular, personalized vaccine strategies targeting patient-specific tumor neoantigens have demonstrated significant promise, although challenges remain in accurately identifying immunogenic targets within highly heterogeneous tumors and overcoming immune evasion mechanisms. Machine learning and deep learning approaches enhance neoantigen prediction by integrating peptide–major histocompatibility complex (MHC) binding, antigen processing, and T cell receptor recognition, thereby improving immunogenicity assessment beyond conventional pipelines. AI-driven mRNA sequence optimization including codon usage refinement and untranslated region (UTR) engineering further enhances protein expression, translation efficiency, and mRNA stability. In parallel, AI-guided modeling of mRNA secondary structures and lipid nanoparticle (LNP) formulations supports efficient intracellular delivery, improved stability, and controlled immune activation. This review provides a structured overview of AI-enabled computational frameworks for mRNA cancer vaccine development and offers practical guidance for integrating in silico predictions with experimental validation. By addressing tumor heterogeneity, antigen processing constraints, and patient-specific immune landscapes, bioinformatics-driven strategies enable more rational and translatable mRNA vaccine design. Collectively, these advances establish a robust foundation for the development of personalized mRNA-based cancer immunotherapies with improved immunogenicity and therapeutic efficacy.

Neurotransmitters: Key regulators of the tumor immune microenvironment.

Comment on " Protein post-translational modifications and tumor immunity: A pan-cancer perspective".

IL-1 family members as regulators of lymphoid type-2 immunity in cancer.

Localized chemo-immunotherapy for HNSCC via CpG-synergized doxorubicin release from injectable TPGS/Na₂CO₃ hydrogel remodeling tumor immunity.

Emerging evidence suggests that the efficacy of immunotherapy in patients with advanced HER2-negative gastric cancer differs between Asian and non-Asian populations. This review examines potential factors contributing to these disparities, including differences in demographic and clinicopathologic characteristics, somatic mutations, molecular subtypes, tumor immunity, Helicobacter pylori (H. pylori) infection, dietary habits, and gut microbiome composition. These factors may serve as predictors of immunotherapy response in gastric cancer patients. For example, the prevalence of molecular subtypes and somatic mutations have been linked to variations in immunotherapy efficacy between Asian and non-Asian populations. In addition, differences in H. pylori infection rates, dietary habits, and gut microbiota composition may influence systemic immune responses, and consequently, immunotherapy outcomes. Understanding the factors contributing to these disparities in immunotherapy response is crucial for optimizing treatment strategies and improving outcomes for patients with gastric cancer. Further research into the mechanisms underlying racial and ethnic disparities in immunotherapy response is needed to identify potential biomarkers predictive of immunotherapy response in diverse patient populations.

Pan-cancer analysis of PDZK1IP1 reveals its role in tumorigenesis and tumor immunity: focused validation in thyroid carcinoma.

Bladder cancer persists as a formidable clinical challenge due to its high recurrence rate, intrinsic chemoresistance, and suboptimal immunotherapy response. Copper-based nanomaterials have emerged as promising therapeutic platforms leveraging distinctive copper redox biology and tumor vulnerabilities to copper-induced cell death mechanisms-particularly cuproptosis. This review systematically analyzes dysregulated copper metabolism in bladder cancer and its mechanistic roles in mediating oxidative stress, ferroptosis, and cuproptosis, while classifying four principal nanomaterial categories: metallic Cu structures, copper-based polymers, copper-based compounds, and copper composites-highlighting their synthesis strategies, physicochemical properties, and therapeutic applications. These platforms facilitate photothermal, photodynamic and chemo-/immunotherapeutic synergies through precise modulation of redox homeostasis and tumor immunity. Despite these advances, key clinical translation barriers including biosafety concerns, pharmacokinetic variability, targeting inefficiency, immune unpredictability, and regulatory hurdles are critically examined. Future directions propose physics-informed material design, biomarker-guided patient stratification, and integrated therapy-monitoring platforms, demonstrating copper-based nanomedicine's significant potential to redefine precision intravesical therapy through mechanistically tailored, translationally optimized strategies.

Although peritumoural visceral adipose tissue (tVAT) is anatomically close to tumours such as colorectal cancer, the immune landscape of this tissue and its functional contribution to tumour immunity remain poorly defined. Here, we performed single-cell RNA analysis on the tVAT from patients with colorectal cancer to map its immune landscape and observed that tVAT exhibited a highly immune-infiltrated microenvironment enriched with lymphocytes, especially tumour-specific CD8⁺ T cells. Mechanistically, tVAT competes with the tumour for these immunocytes by activating the CXCL12-CXCR4 axis to promote tumour immune escape. Moreover, tumour-derived factors induce an adipose-mesenchymal transformation process where the adipose stromal cells trans-differentiated into adipose-derived cancer-associated fibroblasts, which secrete large amounts of CXCL12 in tVAT. Clinically, targeting adipose-tumour interaction substantially enhances diagnostic and therapeutic efficacy of anti-PD-1 therapy. These findings offer an understanding of the dynamic crosstalk between tVAT and tumour immune escape, highlighting the tVAT as a potential target for cancer immunotherapy.

Thrombosis was recognized as a significant cause of morbidity and mortality for prostate cancer (PCa). The potential mechanisms underlying the effect of thrombosis on PCa remain elusive. Retrospective analysis of dual-center clinical data identified thrombosis-PCa correlations. Bioinformatics integration of TCGA-PRAD transcriptomics and thrombosis-related genes enabled construction of a prognostic signature, validated externally. Functional, immune, and drug sensitivity analyses were performed. Experimental validation included IHC, qPCR, IF, in vitro functional assays, and in vivo models. Elevated thrombosis risk strongly correlated with PCa aggressiveness and adverse clinical features. A five-gene risk model stratified PCa patients into distinct survival groups (low-risk: superior outcomes), validated by ROC/Cox analyses as an independent prognostic tool. Findings from functional enrichment, alongside evaluations of immune cell infiltration, immunotherapy responsiveness, and drug sensitivity, reinforced the capacity to accurately forecast the clinical efficacy of precision therapies, as validated by clinical relevance analysis and nomogram development. Immunohistochemistry and qPCR of signature genes revealed marked differences between PCa and adjacent tissues. Importantly, experimental knockdown of VAV2 in 22RV1 cells downregulated prothrombotic inflammatory factors (CXCL8, IL-6, and VEGF). Conditioned media from VAV2-knockdown cells markedly inhibited tube formation in HUVECs and suppressed NETs formation. In vivo, mice administered with conditioned media from VAV2-deficient cells exhibited prolonged PT and APTT, and reduced fibrinogen levels, indicating attenuated coagulation potential. We successfully developed and validated an innovative and robust five-gene signature, seamlessly integrating clinical prognostic parameters for the precise prediction of PCa patients outcomes. This dissertation offers an in-depth exploration of thrombosis, elucidating potential biological mechanisms underpinning therapeutic strategies related to tumor immunity in PCa.

Abstract Background: TNBC is an aggressive breast cancer subtype affecting younger, non-white women in Brazil, associated with higher recurrence and lower survival. Although chemotherapy remains the primary treatment for advanced TNBC, recent advances in immunotherapy highlight the importance of immune biomarkers such as tumor-infiltrating lymphocytes (TILs) and programmed death-ligand 1 (PD-L1) expression in predicting treatment response. TIL subtypes and PD-L1 are important in tumor immunity and treatment response. Their prognostic value and racial differences in Brazil require further investigation. Methods: A retrospective database query was performed within the Brazilian National Cancer Institute to identify women with recurrent or metastatic TNBC treated between 2018 and 2022. Patients were categorized as White or Black/Mixed-race. Biopsy specimens obtained before chemotherapy underwent immunohistochemistry (IHC) assessment using the PD-L1 CPS by 22C3 pharmDx assay, along with markers including CD3, CD4, CD8, CD68, FOXP3, and PD-1. Associations between the prevalence of TILs subtypes and ethnicity were evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan–Meier method. Results: A total of 148 patients with advanced TNBC were included: 44 (29.7%) White and 104 (70.3%) Black/Mixed-race. Median age was similar—White 52.0 years (SD 12.6) and Black/Mixed 51.5 years (SD 13.4). De novo disease was present in 31 (70.5%) White and 81 (77.9%) Black/Mixed patients. Immune marker expressions showed modest differences: median CD3 was 5.0 (IQR 1.0–16.2) in White and 5.0 (1.0–30.0) in Black/Mixed; CD4 median was 10.0 (1.0–16.2) vs. 10.0 (1.0–30.0); CD8 median was 5.0 (1.0–20.0) in both groups. CD68 median was higher in White patients—12.5 (1.0–75.0) vs. 10.0 (1.0–40.0). FOXP3 median was 0.0 (0.0–1.0) in White and 0.0 (0.0–3.0) in Black/Mixed; PD-1 median was 0.0 (0.0–1.0) in White and 1.0 (0.0–1.0) in Black/Mixed. PD-L1 CPS distribution was similar: CPS <1 in 25 (56.8%) White and 58 (55.8%) Black/Mixed; CPS 1–9 in 10 (22.7%) White and 24 (23.1%) Black/Mixed; CPS ≥10 in 9 (20.5%) White and 22 (21.2%) Black/Mixed. Median PFS was 4.6 months (95% CI 3.8–7.7) in White and 5.1 months (4.7–6.4) in Black/Mixed; 2-year PFS rates were 2.8% (0.4–19.4%) and 1.7% (0.3–10.8%), respectively. Median OS was 9.9 months (6.5–13.9) in White and 8.7 months (7.1–11.7) in Black/Mixed; 2-year OS rates were 17.9% (8.8–36.5%) and 6.9% (3.1–15.3%), respectively. Conclusions: In this Brazilian real-world cohort with advanced TNBC, immune marker expression and PD-L1 CPS were similar between White and Black/Mixed-race groups. Minor TIL differences did not affect PFS or OS, indicating comparable immunologic profiles across racial groups and suggesting comparable benefit from immunotherapy. Keywords: Triple-negative breast cancer; tumor-infiltrating lymphocytes; PD-L1; race disparities. Citation Format: J. da Silva, A. dos Santos, L. de Albuquerque, A. Neto, C. da Silva, L. Cerva, I. Small, F. Rodrigues, F. de Macedo, P. Fernandes, L. da Silva, A. de Melo. Real-world comparison of tumor-infiltrating lymphocytes and survival in advanced triple-negative breast cancer across racial groups in brazil [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-12-13.

Head and neck squamous cell carcinoma (HNSCC) is a significant cause of morbidity and mortality worldwide, with limited treatment options for patients with locally advanced disease. CD47 immune checkpoint inhibitors have been used to block the CD47/SIRPa interaction that inhibits antigen-presenting cell phagocytosis, thereby enhancing antigen presentation to cytotoxic T-cells, and have shown promise in combination with anti-PD1 immunotherapy in tumors, including recurrent/metastatic HNSCC. We found that CD47 expression is associated with poor prognosis in HNSCC and explored the anti-tumor activity of an anti-CD47 fusion protein in combination with anti-PD1 and lymphatic-sparing radiotherapy in a locally advanced HNSCC model. In the 4MOSC1 syngeneic HPV-negative HNSCC mouse model, ALX301 (an engineered CD47-blocking SIRPα fusion for murine models) induced complete tumor regression when combined with anti-PD-1, and produced a partial tumor response as a monotherapy. An anti-PD1 immune checkpoint inhibitor in a CD47-null tumor background led to complete tumor regression confirming a key role for CD47 in tumor immunity. ALX301 treated mice demonstrated increased MHC-II expression on dendritic cells within the tumor and upregulation of CD86 co-stimulatory molecule on dendritic cells within the tumor, sentinel lymph nodes, and contralateral lymph nodes. Combination ALX301 and anti-PD1 treatment in an anti-PD1 resistant 4MOSC2 model demonstrated significant tumor regression, enhanced survivability, improved response with neoadjuvant radiotherapy, and greater retention of CD8 + T-cells within the tumor microenvironment. Notably, T-cell receptor sequencing revealed increased shared clonality between the tumor and sentinel lymph nodes of ALX301 treated mice. These data demonstrate that a combination of CD47 blockade and anti-PD1 therapy enhances tumor antigen presentation and immune cell infiltration, while further improving anti-tumor responses in combination with tumor-targeted radiotherapy. This study provides support for the rational design of combinatorial immunoradiotherapy, using anti-CD47 inhibitors and anti-PD1 therapy, in a clinical trial targeting locally advanced HPV-negative HNSCC.

Low immunogenicity and highly immunosuppressive tumor microenvironment (TME) present major challenges in immunotherapy, as they restrict T lymphocyte infiltration and activation. Although ferroptosis induction has emerged as a promising approach for enhancing tumor immunogenicity and promoting T cell recruitment, its efficacy is frequently compromised by cholesterol-driven T cell functional exhaustion. To address these limitations, we engineered tumor-targeting, TME-responsive, and size-switchable supramolecular nanoprodrugs that enable multidimensional immune activation. Nanoprodrugs orchestrate a sophisticated cascade of immune activation through four synergistic mechanisms: 1) size-switchable disassembly upon glutathione/ cholesterol exposure for deep tumor penetration; 2) redox imbalance driven by reactive nitrogen species accumulation and glutathione depletion via the synergistic action of oxaliplatin, ferrocene, and RRx-001 for ferroptosis augmentation; 3) immunogenic cell death induction via ferroptosis-apoptosis to initiate tumor immunity cycle, promoting T cell infiltration; and 4) T cell function reinvigoration with the downregulation of programmed cell death protein 1 and T-cell immunoglobulin 3 expression through cholesterol depletion in TME. This integrated approach achieved primary and distant tumor growth suppression, established durable immune memory against recurrence, and systemically enhanced the antitumor immunity. By concurrently targeting tumor immunogenicity, TME immunosuppression, and T cell exhaustion, this multidimensional strategy represents a transformative advancement in cancer immunotherapy.

Abstract Purpose: To assess the potential of an estrogen receptor beta (ERβ) agonist as an immunotherapy for triple negative breast cancer (TNBC). Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of ERα, PR, and HER2 expression with limited treatment options. Although immune checkpoint inhibitors (ICIs) have shown some benefit, response rates remain low in advanced-stage TNBC. This highlights a critical gap in our understanding of oncogenic mechanisms, especially those leading to immunosuppressive tumor microenvironment (TME), and underscores the urgent need for innovative therapeutic targets to improve patient outcomes. Estrogen receptor beta (ERβ), expressed in approximately 30% of TNBCs, is a subtype of estrogen receptor with known anti-tumor properties. While prior studies have established ERβ’s tumor-suppressive role, its effect on the TME remains poorly defined. Despite recently observed clinical associations of ERβ with improved prognosis and immune-related markers, the mechanisms by which ERβ impacts immune cell recruitment, phenotype, and response to immunotherapy have not been thoroughly studied. Here, we aim to define how ERβ regulates immune activity in TNBC and to evaluate its utility as an immunotherapeutic target and biomarker. Methods: To test whether tumor-specific ERβ activity contributes to an immunostimulatory tumor microenvironment, we generated unique syngeneic models and patient-derived xenografts (PDXs) of TNBC with altered ERβ expression and investigated differences in tumor growth and immunophenotype using flow cytometry and immunohistochemistry. Single-cell and spatial genomics were used to study how ERβ alters signaling in tumor cells, affecting effector cells to reduce immunosuppression. To determine whether activating ERβ with agonists further stimulates tumor immunity and inhibits tumor progression, we administered the ERβ agonist LY500307, which is clinically tested in other diseases. ERβ targets and downstream signaling were validated through transcriptional and functional studies in isolated immune cells and cocultures. Lastly, we correlated ERβ’s expression and function with immune signatures and clinical outcome by deconvoluting sequencing data from TCGA-profiled breast cancers and through spatial proteomics analysis of a tissue microarray with TNBC samples. Result: We observed that activated tumor-specific ERβ leads to slowed tumor growth and a less immunosuppressive TME, which is characterized by a significant reduction in tumor-associated M2-like macrophages and increased cytotoxic T cell activity. RNA-seq and cytokine profiling of LY500307-treated ERβ-expressing breast cancer cells identified key target cytokines as downstream mediators, particularly CXCL2, CCL5, CSF2, and IL4 that regulate macrophage function and antigen presentation during tumor adaptive immunity. Preliminary clinical analysis revealed an inverse correlation between ERβ expression and the frequency of myeloid cells that predicted a worse patient outcome, reinforcing the prognostic significance of the receptor. Conclusions: By integrating spatial and single-cell genomics, and immune-functional assays, this study uncovers important functional and mechanistic features of the immunomodulatory role of ERβ. Our findings aim to transform our understanding of ERβ as a tumor suppressor in the immunosuppressive TME of TNBC and could help identify predictive biomarkers and therapy targets to improve patient outcomes. Citation Format: K. A. Zambo, F. Nikolos, H. Nagandla, K. Cap, A. Phillips, W. Qian, J. Qian, K. Chan, J. Chang, C. Thomas. Targeting ERβ signaling as a novel immunotherapeutic strategy in TNBC [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-12-03.

Tumor immunity and metabolism are interconnected through the tumor microenvironment (TME), with RNA modifications playing pivotal epigenetic regulatory roles. N4- acetylcytidine (ac4C) is the first acetylated modification identified on eukaryotic RNAs, and N- acetyltransferase 10 (NAT10) is the key enzyme catalyzing this modification, depositing ac4C on transfer RNA(tRNA), ribosomal RNA(rRNA), messenger RNA(mRNA), and long non-coding RNA(lncRNA) via its specific localization and expression. However, its systematic functions in tumor immunity and metabolic reprogramming have not been comprehensively summarized for clinical translation. This review systematically synthesizes recent research on NAT10-mediated ac4C modification in oncology, covering data from cell experiments, animal models, and clinical sample analyses across multiple tumor types (e.g. breast cancer(BC), liver, cervical cancer(CC). It integrates findings on NAT10's dual enzymatic activities, subcellular localization, regulation of cell cycle and DNA damage repair, mechanisms in TME remodeling and metabolic reprogramming, as well as preclinical progress of NAT10 inhibitors. NAT10 possesses dual enzymatic activities of protein acetylation and RNA acetylation. Its subcellular localization is redistributed in tumor tissues, which is closely associated with tumorigenesis and progression. In TME remodeling, the NAT10-ac4C axis regulates inflammasome activation, suppresses T-cell function, promotes M2 macrophage polarization, andrecruits tumor- associated macrophages, thereby creating an immunosuppressive microenvironment.In metabolic reprogramming, this axis drives glycolysis by stabilizing hexokinase 2(HK2)/lactate dehydrogenase A (LDHA) mRNA, regulates amino acid metabolism through the Khib-ac4C cascade, and modulates fatty acid metabolism and ferroptosis resistance. Furthermore, high NAT10 expression is associated with chemotherapy and radiotherapy resistance in various tumors, and its inhibitor Remodelin has shown synergistic antitumor effects when combined with immune checkpoint inhibitors in preclinical studies. NAT10-mediated ac4C modification is a critical regulatory node integrating tumor immunity and metabolism, serving as a promising potential target for precision cancer therapy. Current research still faces challenges such as insufficient sensitivity and specificity of ac4C detection technologies, unclearcell-type-specific mechanisms of NAT10, limited delivery efficiency of inhibitors, and the existence of compensatory pathways. Future research should focus on optimizing ac4C detection technologies, clarifying cell-type-specific mechanisms, developing targeted delivery systems, and further exploring the clinical translational value of combining NAT10-targeted therapy with immune checkpoint blockade, so as to provide new strategies and technical support for cancer treatment.

Clonal hematopoiesis (CH), marked by somatic mutations in a blood cell clone, is common in aging and is associated with an increased risk of future leukemia as well as nonhematologic diseases. In solid tumors, the presence of CH is linked to faster cancer progression and poor outcomes, yet its role in tumor immunity is complex. Previous studies implicated CH, particularly driven by TET2 mutations, in creating a myeloid-rich, proinflammatory immunosuppressive tumor microenvironment (TME), whereas TET2 disruption enhanced the performance of chimeric antigen receptor T-cell therapy. In this issue of Cancer Research, Rondeau and colleagues investigated the role of TET2-CH in promoting response to immune checkpoint blockade (ICB). In a model of hematopoietic Tet2 inactivation in mice implanted with syngeneic flank tumors, the authors found increased efficacy of anti-PD-1 ICB, which required both myeloid and T cells. Mechanistically, Tet2-deficient T cells were biased toward memory states, curbing exhaustion and regulatory phenotypes, whereas myeloid cells shifted from immunosuppressive to costimulatory programs with PD-1 blockade. Consistently, in patients with colorectal cancer and melanoma, TET2-CH was associated with an immune-rich TME and greater odds of clinical benefit from ICB. These findings suggest that TET2-CH may serve as a biomarker of accentuated cancer immunotherapy response, providing novel insights into its role in the TME. See related article by Rondeau et al., p. 845.

Cancer causes millions of deaths globally every year. At its later stages, cancers are primarily treated with systemic therapies which do not provide an effective cure; the remaining cancer cells ultimately acquire drug resistance, relapse, and metastasize. In particular, polyploid giant cancer cells (PGCCs), which arise in response to diverse cellular stressors such as therapeutic pressure, modulate the tumor microenvironment (TME) and immunity involved in cancer development. However, without the knowledge of well-established signaling cascades targeting PGCCs, the current treatment options for these cells remain limited. This review provides a summary of the latest research associated with PGCC formation and treatment outcomes in common metastatic cancers. In addition, we highlight how some traditional Chinese medicine (TCM) and their bioactive compounds may serve as prospective agents for arresting PGCCs through cell cycle regulation, cell death induction, and TME modulation. Specifically, we identify how these processes are closely associated with the initiation, self-renewal, and termination phases of the PGCC life cycle. Based on the principle in TCM of "strengthening vital qi to eliminate pathogenic factors," the most efficacious herbs for counteracting PGCCs have been identified as Coptis chinensis, Oldenlandia diffusa, Scutellaria baicalensis, Salvia miltiorrhiza, Curcuma longa, Astragali radix, and Panax ginseng. The bioactive compounds of these herbs include berberine, oleanolic acid, wogonin, tanshinone IIA, curcumin, Astragaloside IV, and ginsenoside Rh2. Given the multi-target characteristics of TCM, network pharmacology was performed to allow for an integrative approach to elucidating underlying mechanisms. In particular, TCM administration may modulate both the p53 signaling pathway and cell cycle-related proteins. This, in turn, alleviates PGCC-induced tumor recurrence and resistance. Collectively, this review emphasizes the central role of PGCCs in advanced cancer progression while strengthening the mechanistic insights of TCM in PGCC-oriented therapy.

circSERINC3 facilitates STAT3-CDK5 crosstalk to orchestrate immunosuppressive microenvironments in pancreatic Cancer.

Lack of pre-clinical models that simulate the complex TME and translate to human immunity is list as the top one challenge in the area of cancer immunotherapy development. While newly emerging organoid models play a crucial role in promoting the development of precision medicine in cancer immunotherapies. With the aid of experimental techniques and co-culture models of immuno-oncology, researchers have made progress in modeling tumor microenvironment (TME) with organoid-immune co-culture technologies to enhance the cellular complexity of the in vitro models, thus helping to improve existing immunotherapies, identify new immunotherapies and find reliable markers to predict the efficacy of immunotherapies for patients with cancer. In the review, we present an overview of the development of the different methods of three-dimensional (3D) patient-derived tumor organoids (PDTOs) modeling TME to study the interaction of tumor with cancer-associated fibroblasts (CAFs), lymphoid cells and myeloid immune cells. Besides, their methods and application in screening for efficacy of pharmacological immunotherapy and cellular immunotherapy in a personalized manner have also been summarized in the review. Moreover, we describe the applications of PDTOs modeling TME in specific cancer types and then summarize their contributions to the development of tumor immunity in different types of cancers. By centering on PDTOs' ability to capture individual tumor-immune biology, the review offers a comprehensive, personalized perspective of PDTO-immune co-culture models, making it a critical resource for researchers, clinicians, and drug developers aiming to advance precision immunotherapy.

The apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) family was first defined as an innate antiviral defense system, but the APOBEC3 subfamily (APOBEC3s) is now recognized as a major endogenous source of somatic mutagenesis in cancer. APOBEC3s enzymes, particularly APOBEC3A and APOBEC3B, generate characteristic mutation patterns that promote genomic instability, clonal evolution, and adaptation to therapy. Beyond driving tumor evolution, APOBEC3 activity reshapes antitumor immunity in solid cancers. APOBEC3-induced mutations increase tumor mutational burden and create neoantigens that can enhance CD8+ T-cell infiltration and interferon signaling. However, sustained APOBEC activation may also reinforce immunosuppressive circuits: through chronic inflammation and PD-1/PD-L1-interferon signaling, tumors can induce T-cell dysfunction, immune escape, and resistance to immune checkpoint blockade. This functional ambivalence has sparked debate over whether APOBEC3s should be inhibited to limit genomic instability, leveraged to enhance tumor immunogenicity, or modulated dynamically in a context-dependent manner. This review outlines the immune landscape and biochemical characteristics of the APOBEC3 family and situates these features within broader cancer-related disease contexts. APOBEC3-mediated mutagenesis is discussed as a mechanistic link between genomic instability and tumor-immune crosstalk in solid tumors, with emphasis on its relationships to immunoediting, immune checkpoint pathways, and therapeutic responses. Context-dependent associations of APOBEC3 activity with immune activation or immune evasion are also considered, together with their implications for strategies that modulate this pathway.