Neuroregulation as a modulatory force in immune checkpoint inhibitor resistance: mechanistic neuro-immune crosstalk informing biomarker-led diagnosis and targetable therapeutic sensitization

Immune checkpoint inhibitor (ICI) resistance remains a major challenge. This review discusses emerging evidence that neuroregulation constitutes an underrecognized regulatory layer in ICI resistance and summarizes its mechanistic, biomarker, and therapeutic implications. Mechanistically, neural components can modulate antitumor immunity through signaling, structural, spatial, and metabolic routes. Neural signaling may contribute to T-cell dysfunction by stabilizing exhausted phenotypes, increasing the expression of inhibitory receptors, and suppressing effector cytokine production. Neuroglial cells and neuropeptides further exacerbate immunosuppression through the induction of regulatory T cells and the reprogramming of myeloid cells. Beyond causing functional impairment, neuroregulation alters the spatial distribution of immune cells by inhibiting chemokine networks essential for the recruitment of dendritic cells and cytotoxic T cells, thereby promoting immune-excluded and immune-cold tumor states. Neural injury creates perineural immunosuppressive niches enriched in immunoregulatory tumor-associated macrophage states and regulatory T cells, which can extend into the broader tumor microenvironment and restrict CD8 + T-cell infiltration and function. Neural inputs also reshape the metabolism of tumor and immune cells, establishing neuro-metabolic-immune circuits that limit effector cell fitness and reinforce ICI resistance. Therapeutically, pharmacological targeting of neural pathways, along with emerging bioelectronic and ex vivo neuro-immune strategies, may enhance the efficacy of ICIs across various tumor models. Neural abundance and injury signatures also emerge as potentially clinically relevant biomarkers that complement immune-centric predictors of response. Overall, neuroregulation provides a biologically coherent and potentially targetable framework for understanding and overcoming ICI resistance.