Targeting multidimensional nociceptor-tumor interactions to mitigate immune evasion of cancer.

Sensory neurons were traditionally viewed as passive detectors of noxious stimuli and mediators of cancer-associated pain. However, accumulating evidence has identified nociceptive sensory neurons as active regulators of tumor biology and immunity in solid tumors. In this review, we summarize recent advances in cancer neuroscience, detailing how tumor-infiltrating nociceptive neurons undergo functional reprogramming to actively participate in tumorigenesis. We first discuss local intratumoral crosstalk, highlighting the direct regulation of immune cells by nociceptive neurons and their indirect immunomodulatory effects through tumor cells and stromal components. We then examine emerging evidence that nociceptive signaling extends beyond the primary tumor through cross-organ neuroimmune communication, particularly via tumor-draining lymph nodes, thereby contributing to systemic immune suppression. Finally, we highlight conventional pharmacological approaches and selective delivery-based strategies aimed at disrupting this neuroimmune axis. Together, this review clarifies the local and systemic roles of nociceptive sensory neurons in tumor immune regulation and discusses their potential as therapeutic targets in cancer.