Authors
Peng-Yu Zhao, Kun Wu, Zi-Xiang Jin, Xu-Zhao Li, Wei-Lin Jin, Wioletta Rozpędek-Kamińska
Published in
Pharmacological research. Pages 108435. Sep 06, 2026. Epub Sep 06, 2026.
Abstract
Cancer neuroscience has expanded the conceptual landscape of tumor biology by revealing that nerves are not passive bystanders within malignant tissues, but active regulators of tumor progression, immune surveillance, and therapeutic response. Among neural components of the tumor microenvironment, nociceptive sensory neurons have emerged as critical interfaces between tissue injury, inflammation, cancer-associated pain, and immune regulation. This review proposes that nociceptive neuron-driven immune escape represents a tissue-level pathological process positioned at the intersection of cancer neuroscience, tumor immunology, and immunometabolism. We discuss how tumor-associated inflammatory mediators, extracellular acidosis, mechanical stress, metabolic perturbations, and axon-guidance programs activate nociceptors and induce the release of calcitonin gene-related peptide (CGRP) and related neuropeptides. Through receptor activity-modifying protein 1-containing receptor complexes, CGRP can suppress CD8⁺ T-cell receptor signaling, promote exhaustion-associated transcriptional and metabolic programs, impair dendritic cell function, and reinforce suppressive myeloid and regulatory immune compartments. We further examine how tumor cells may co-opt the ATF4-SLIT2-CGRP axis to establish cross-organ neuroimmune circuits extending to tumor-draining lymph nodes, thereby weakening antigen presentation, T-cell priming, and responsiveness to immune checkpoint blockade. Finally, we consider lactate accumulation and extracellular acidification as parallel immunometabolic pressures that may consolidate nociceptor-associated immune dysfunction by constraining T-cell bioenergetic fitness, promoting suppressive immune states, and potentially modulating sensory-neuron activity. Rather than defining a fixed linear pathway, we conceptualize the nociceptor-CGRP-lactate axis as an integrative neuroimmune-metabolic framework in which partially independent neural and metabolic processes converge on shared mechanisms of immune escape. This framework provides a translational rationale for evaluating combined neural, metabolic, and immune checkpoint-directed interventions in cancers characterized by neural involvement, metabolic suppression, and immunotherapy resistance.
PMID:
42702340
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.
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