Cancer immunotherapy has transformed oncology, yet its clinical efficacy is often limited by immune evasion within the tumor microenvironment (TME). Regulatory T cells (Tregs), a key immunosuppressive lineage, potently inhibit effector T-cell proliferation and activation, thereby dampening antitumor immune responses. Tregs are frequently enriched in diverse solid tumors, and their abundance correlates with poor prognosis, increased tumor invasiveness, and therapeutic resistance. A major mechanism driving this enrichment is the chemokine-chemokine receptor axis. Tumor cells, along with other stromal and immune cells in the TME, secrete chemokines including CCL22, CCL20, and CXCL12, which bind to CCR4, CCR6, and CXCR4 on Tregs and direct their recruitment and activation within the TME. This establishes an immunosuppressive niche that promotes tumor growth, facilitates metastasis, and reduces responsiveness to immunotherapy. This review consolidates eight experimentally validated chemokine-Treg axes from 2005 to 2025, with each study annotated by tumor type and represented by the highest observed level of evidence. A systematic representation illustrates how these axes mediate Treg-driven immunosuppression and maps their prevalence across cancers. Focusing on these axes provides mechanistic insights, highlights potential therapeutic targets, and identifies predictive biomarkers. Strategies targeting the chemokine-chemokine receptor axes, including selective receptor blockade, combination with immune checkpoint inhibitors, and omics-based approaches to resolve Treg heterogeneity, offer avenues to reprogram the immunosuppressive TME and enhance antitumor immunity.

Radiotherapy (RT) remains a cornerstone of cancer treatment, yet its efficacy is often limited by tumor recurrence and resistance. Emerging evidence underscores the pivotal role of the tumor microenvironment (TME) in this process. RT-induced vascular damage exacerbates hypoxia, a key driver of resistance, while activation of cancer-associated fibroblasts promotes fibrosis and extracellular matrix remodeling that shield tumor cells. Furthermore, RT elicits a complex immune response, capable of both immunogenic cell death and fostering an immunosuppressive milieu enriched with regulatory T cells and myeloid-derived suppressor cells. We discuss the mechanisms through which these TME alterations, hypoxia, fibrotic signaling, and immune evasion, collectively contribute to RT resistance and recurrence. In this review, we summarize current knowledge on how RT remodels the TME, focusing on its dualistic impact on vascular integrity, stromal activation, and immune regulation. Finally, we outline the promising therapeutic strategies in overcoming TME-mediated resistance, including vascular normalization, targeting hypoxia-inducible factors, and combining RT with immunotherapies such as immune checkpoint blockade. Overall, a deeper understanding of TME dynamics post-RT is crucial for developing novel combination therapies to improve clinical outcomes.

Lung cancer remains the second most prevalent malignancy worldwide and is characterized by persistently high incidence and mortality rates. As the disease progresses, most patients develop immune evasion and metastatic dissemination, which represent major threats to overall survival. The advent of targeted therapies and immunotherapies has fundamentally reshaped the clinical management of lung cancer; however, therapeutic resistance and limited durability of response remain critical challenges. Lactylation has recently emerged not only as a novel post-translational modification but also as a potential therapeutic vulnerability in lung cancer. By modulating the activity, stability, and transcriptional functions of both histone and non-histone proteins, lactylation reshapes tumor metabolism, immune evasion, and resistance-associated signaling pathways. Importantly, growing evidence suggests that therapeutic strategies targeting lactylation-related pathways may offer new opportunities to improve outcomes in patients with advanced lung cancer and overcome acquired resistance to existing therapies. In this review, we systematically delineate the molecular mechanisms underlying lactylation, with particular emphasis on the enzymatic machinery governing lactylation dynamics and its regulatory network. We synthesize current evidence describing how lactylation-driven signaling programs contribute to lung cancer progression, immune escape, and treatment resistance, highlighting the complex interplay between lactylation pathways and lung cancer pathobiology. Furthermore, we critically evaluate the translational potential of lactylation sites and their downstream effectors as diagnostic and prognostic biomarkers, as well as actionable therapeutic targets. Collectively, these findings support the concept that targeting lactylation-associated regulatory circuits represents an emerging and potentially more selective therapeutic strategy for lung cancer. Nevertheless, clinical translation remains constrained by the lack of specific intervention tools, standardized detection methodologies, and robust human data. Future studies should prioritize the development of precise lactylation-targeted approaches and large-scale, longitudinal clinical investigations to validate their clinical value and overcome current translational bottlenecks.

The development and metastasis of tumors depend on the highly complex and heterogeneous tumor microenvironment (TME). Synergistic pulsed electric fields refer to a sequential combination of high-voltage nanosecond pulses and low-voltage microsecond pulses. No systematic research has been reported on the ameliorative effect of this field on the TME and the related mechanisms. This study used tumor-bearing models established with male Balb/c nude mice and male C57BL/6 mice as research subjects. At the molecular, cellular, and tissue levels, this study employed Masson staining, immunofluorescence staining, immunohistochemical staining, and in vivo small animal imaging technology. This study multi-angle analyzed the effect of synergistic pulse treatment on key physical and chemical indicators of the tumor microenvironment (TME) for the first time. It also explored the effect of its combined application with exogenously injected natural killer (NK) cell therapy. Experimental results showed that synergistic pulse treatment could effectively improve the physical properties of the TME. It reduced tumor stiffness and density, and alleviated the hypoxic state. Meanwhile, it could stimulate the body's anti-tumor immune response and promote the infiltration of cytotoxic immune cells into tumors. Furthermore, this pulse could significantly promote the enrichment and intratumoral penetration of exogenously injected NK cells at tumors, thereby boosting cellular immunotherapy efficacy. This study demonstrated that synergistic pulsed electric fields can potentially remodel the TME and enhance immune cells' anti-tumor effect for tumor ablation. It provides a new technical direction for inhibiting tumor recurrence and metastasis and demonstrates potential for clinical translation.

Small cell lung cancer (SCLC) remains one of the most aggressive malignancies, characterized by limited therapeutic options and persistently poor survival outcomes. This review summarizes recent advances in understanding the immunosuppressive tumor microenvironment, emerging therapeutic strategies, and biomarker-driven approaches that may enable more precise treatment. The SCLC microenvironment is dominated by suppressive immune cell populations-including regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells-that collectively inhibit antitumor immune responses. Integrative molecular and immunologic profiling has defined four transcription factor-driven subtypes, each exhibiting distinct immune phenotypes and differential responses to therapy. Although current immunotherapies have conferred meaningful yet modest clinical gains, combining PD-1/PD-L1 blockade with chemotherapy has improved survival in extensive-stage disease, and CTLA-4 inhibition demonstrates potential within combination regimens. Beyond immune checkpoint blockade, novel therapeutic modalities such as DLL3-targeted antibody-drug conjugates, bispecific T-cell engagers, and emerging B7-H3-directed strategies have shown encouraging activity in treatment-refractory settings. However, conventional biomarkers-including PD-L1 expression and tumor mutational burden-remain unreliable in SCLC, and the mechanisms underlying therapeutic resistance are still insufficiently understood. Future efforts should prioritize the refinement of molecular subtyping frameworks, the establishment of robust biomarker-guided patient stratification, the elucidation of resistance pathways, and the development of precision immunotherapies tailored to SCLC heterogeneity.

Given the abundant stroma of the liver and that cirrhosis or hepatic fibrosis is the premalignant condition of most hepatocellular carcinomas (HCC), underscores the critical interaction between extracellular matrix (ECM) stiffness and the tumor microenvironment (TME) in the initiation, progression, and immunotherapy of HCC. This review presents a comprehensive exploration of the factors that regulate matrix stiffness, including the activation of cancer-associated fibroblasts (CAFs), the excessive deposition of ECM proteins, and cross-linking. Furthermore, this review explores the underlying molecular pathways through which matrix stiffness affects the prevalence of tumors and immune cells. Based on these premises, we delve into the potential targets and roles of pharmacological interventions targeting matrix stiffness in HCC and its immunotherapy, and highlight the considerable potential of biomaterials for the development of ECM stiffness-targeted agents. The potential exists for such agents to enhance the efficacy of immunotherapy and prolong the survival of patients diagnosed with HCC.

Radiation therapy (RT) offers a tool to enhance immune checkpoint inhibitor (ICI) efficacy, yet its immunomodulatory potential remains poorly understood. Here, we investigated how RT dose-fractionation regimens shape local and systemic antitumor immunity.

A hematopoietic stem cell-humanized NOG mouse model was established, bearing ICI-responsive renal cell carcinoma (RCC) or ICI-resistant non-small cell lung cancer (NSCLC) and melanoma. Mice were treated with RT using different dose-fractionation regimens in combination with ICI. Tumor growth, systemic immune responses, and abscopal effects were assessed. Immune remodeling was characterized by flow cytometry, immunohistochemistry, and RNA-sequencing analyses.

Immuno-RT (iRT) improved tumor control across models, and induced abscopal effects in ICI-resistant models, especially in NSCLC, where 3x8 Gy combined with ICI triggered systemic responses, increased circulating monocytes and remodeled the tumor microenvironment (TME). Late-stage responses in ICI-resistant tumors were marked by low immune infiltration but enriched signatures of immune memory, cGAS/STING pathway, damage associated molecular patterns, cell death, and metabolic reprogramming. Our findings support RT as a strategy to overcome ICI resistance and validate humanized mice as a translational model for iRT research.

Extracellular vesicles (EVs) have emerged as pivotal mediators of intercellular communication and have attracted considerable scientific interest in recent years owing to their critical roles in tumor immunity and drug resistance. This review offers a comprehensive overview of the mechanisms by which EVs function within the tumor microenvironment, focusing on their involvement in immune evasion, tumor progression, and the development of resistance to therapeutic agents. By summarizing recent research advances, this review highlights the potential of EVs as diagnostic biomarkers and therapeutic targets and emphasizes their significance in improving treatment efficacy and overcoming clinical resistance. This review also outlines future research directions to clarify the multifaceted roles of EVs in cancer biology and facilitate the development of novel therapeutic approaches to enhance patient outcomes.

Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) is orchestrated not only by tumor-intrinsic genomic alterations but also by dynamic reprogramming of the tumor microenvironment (TME). This review introduces the tumor-immune spatiotemporal co-evolution paradigm, which reframes mCRPC resistance as an ecosystem-level adaptation unfolding across temporal (disease stage) and spatial (niche architecture) dimensions. We synthesize clinical and multi-omics data to map a probabilistic evolutionary trajectory from an immune-permissive state, through suppressive niche consolidation, to a terminal immune desert phenotype. In this review, we systematically apply the Oxford Centre for Evidence-Based Medicine (OCEBM) 2011 criteria to this field, grading all mechanistic claims to explicitly distinguish peer-reviewed, validated findings (Level 1-2b) from speculative hypotheses (Level 3-4), and delineate 5 evidence-graded core conclusions of the tumor-immune co-evolution paradigm. We delineate how spatially organized cancer-associated fibroblast (CAF) subsets architect immunosuppressive niches and engage in reciprocal metabolic symbiosis with tumor cells, and redefine therapeutics as dominant selective pressures that drive clonal-stromal co-selection to explain cross-resistance across treatment modalities. To translate this paradigm, we propose an integrative closed-loop "Dynamic Monitoring-Mechanistic Parsing-Synergistic Intervention" framework, with concrete, clinically actionable strategies grounded in 2024-2025 peer-reviewed prostate cancer research. This framework advocates for longitudinal ecological auditing of the TME to rationally guide mechanistically orthogonal combination therapies. Our objective is to provide a rigorously evidence-based roadmap for transforming mCRPC into a chronically manageable condition through precision ecological intervention, offering a novel, actionable perspective to advance prostate cancer immunotherapy and overcome immune evasion for researchers and clinicians in the field of cancer immunology.

Intravascular papillary endothelial hyperplasia (IPEH) is a rare, benign, non-neoplastic vascular lesion resulting from reactive endothelial proliferation associated with thrombus organization. Although uncommon in the oral cavity, IPEH may clinically mimic malignant neoplasms, frequently presenting as a nodular or ulcerated lesion and posing a diagnostic challenge. Histopathological examination remains the gold standard for diagnosis and plays a crucial role in the differential diagnosis, helping to avoid unnecessary aggressive treatment. Surgical excision with clear margins is generally considered the treatment of choice; however, evidence regarding alternative management strategies is scarce. We report the case of a 74-year-old woman who presented with an ulcerated lesion on the right lateral border of the mobile tongue, clinically highly suspicious for oral malignancy due to its morphology and patient-related risk factors. Histopathological analysis revealed intravascular papillary endothelial hyperplasia. Given the benign diagnosis, the patient's significant systemic comorbidities, severe cognitive impairment, and the high risk associated with surgical treatment and postoperative care, a conservative management strategy based on watchful waiting was deliberately chosen. No additional imaging studies were performed, as they were not expected to influence clinical decision-making. During follow-up, the lesion remained clinically stable without signs of progression. This case underscores the importance of considering IPEH in the differential diagnosis of tongue lesions and highlights that, in carefully selected patients, conservative management may represent a valid alternative to surgery, thereby preventing overtreatment of benign vascular lesions that clinically simulate malignancy.