The nervous system has emerged as a critical regulator of tumor biology. Over the past 2 decades, accumulating evidence has given rise to the rapidly expanding field of cancer neuroscience, revealing that neural circuits actively shape tumor initiation, progression, metastasis, prognosis, and therapeutic response. While the nervous system comprises both central and peripheral components, increasing attention has focused on the peripheral nervous system (PNS) as a key mediator of tumor–host interactions within the tumor microenvironment (TME). Autonomic (sympathetic, parasympathetic, and enteric) and sensory neural pathways interact dynamically with tumor cells, immune cells, glial cells, and other stromal components, influencing tumor growth, invasion, metastasis, and immune regulation through diverse cellular and molecular mechanisms. In addition, environmental and patient pathophysiological factors—including environmental stress, psychological states, pain, microbiota, aging, metabolic status, and lifestyle behaviors—can further modulate nerve–cancer interactions and reshape the tumor ecosystem. In this review, we systematically organize PNS–cancer interactions within the TME across 3 integrative dimensions: pathological phenotypes, cellular components, and modes of communication, thereby providing a conceptual framework for understanding the mechanistic landscape of cancer neuroscience. This structured perspective highlights the diverse modalities of nerve–tumor communication, identifies key modulatory factors influencing these interactions, and discusses emerging therapeutic strategies targeting nerve–cancer signaling.

Radiopharmaceutical therapy (RPT) is a pivotal modality in cancer treatment, with its efficacy substantially modulated by the tumor microenvironment (TME). The TME regulates RPT penetration and influences therapeutic outcomes. Concurrently, RPT actively reconfigures the TME by enhancing immune activation and partially reversing immunosuppression. Specifically, RPT induces tumor cell senescence and immunogenic cell death, and catalyzes immune activation. RPT diminishes immunosuppressive elements, including regulatory T cells and tumor-associated macrophages, and augments populations of CD8⁺ T cells and natural killer cells, thereby fostering a more immunostimulatory TME. Additionally, RPT modulates critical cytokines and upregulates immune checkpoint molecules, bolstering anti-tumor immunity. Nevertheless, pathological features like hypoxia and extracellular matrix stiffness within the TME can hinder RPT biodistribution and therapeutic efficacy. Strategically targeting the TME through approaches, such as fibroblast depletion, hypoxia mitigation, metabolic reprogramming, nerve-immune-cancer interactions, or nanocarrier drug delivery, can amplify RPT effectiveness. Combination immunotherapies that integrate RPT with immune checkpoint inhibitors, chimeric antigen receptor (CAR)-T cells, or cancer vaccines have demonstrated enhanced anti-tumor responses and survival advantages in malignancies such as prostate cancer and neuroendocrine tumors. Given the complexity and heterogeneity of the TME, emerging strategies, including radiation-responsive nanocarriers, CAR-T cells engineered to secrete radiosensitizers, senolytic therapies, and artificial intelligence-driven multimodal data integration, are promising in addressing the challenges and refining precision cancer therapy. In summary, the TME serves as a critical bridge between RPT and immunotherapy; elucidating the interplay among these three elements is essential for advancing combination strategies.

Clear cell renal cell carcinoma (ccRCC) is characterized by VHL-HIF pathway alterations, lipid remodeling, abnormal angiogenesis, and marked immune heterogeneity. These features create a highly vascular yet unevenly perfused microenvironment in which vascular dysfunction, hypoxia, stromal barriers, and myeloid clearance influence whether cell death becomes immunologically productive. Although immune checkpoint inhibitor combinations, vascular endothelial growth factor receptor tyrosine kinase inhibitors, and HIF-2α inhibitors have improved outcomes, primary and acquired resistance and discordant responses among lesions remain common. Bulk PD-L1 expression, immune-cell abundance, and cell-death-related transcript signatures do not resolve this heterogeneity. Following current nomenclature, regulated cell death (RCD) is the mechanistically preferred umbrella term; we retain programmed cell death (PCD) in the conceptual label because it remains widely used in the RCC oncology literature, while requiring RCD execution-level evidence for mechanistic claims. Single-cell and spatial multi-omics studies increasingly show that the identity of the dying cell, execution of the death program, accessibility of death-derived material, and the recipient immune cells operate as a coupled local system. We define a PCD-associated immune niche as a spatial tissue state in which representative, non-exclusive immune-routing axes can direct tumor-cell death toward cDC1-mediated cross-presentation and adaptive antitumor immunity, TAM-dominant efferocytosis and tissue repair, or intermediate mixed states. This Review focuses predominantly on ccRCC, evaluates ferroptosis, apoptosis, pyroptosis, necroptosis, and PANoptosis, and briefly considers emerging RCD modalities for which ccRCC evidence is less mature. We further propose composite spatial biomarkers and mechanism-guided combinations that link cellular source, execution evidence, immune routing, and clinical outcome.

Robot-assisted minimally invasive surgery provides stable visualisation and manipulation, but direct access to local tissue state remains limited. Lesion b