Tumor innervation drives cancer cell plasticity and immune evasion through the SLPI-GZMB axis.

Peripheral nerves contribute to tumor progression, but the mechanisms by which neural signals regulate cancer cell plasticity and immune resistance remain unclear. Using a paired murine model of intraneural and nonintraneural tumor growth with single-cell RNA sequencing, we identified a nerve-associated cancer cell state marked by increased expression of secretory leukocyte protease inhibitor (SLPI). SLPI was elevated in intraneural tumors and in human tumors with perineural invasion. Sensory neuron-derived substance P (SP) induced SLPI secretion through tumor cell TACR1, whereas sensory denervation or TACR1 blockade reduced SLPI production. SLPIhigh cancer cells were enriched for WNT/β-catenin and stemness programs. Consistent with this, SLPI increased β-catenin and c-MYC expression, expanded ALDH+ stem-like cells, and enhanced mammosphere formation, whereas Slpi deletion reduced stemness and impaired tumor growth in vivo. SLPI also limited immune-mediated tumor cell killing. Proteomic and biochemical analyses identified granzyme B as a direct SLPI-binding partner, and SLPI inhibited granzyme B-dependent cleavage of caspase-3 and gasdermin E, thereby reducing cytotoxic lymphocyte-induced cell death. In immunocompetent mouse models, pharmacologic inhibition of the upstream SP-TACR1 pathway with aprepitant synergized with anti-PD-1 therapy. In clinical datasets, high SLPI expression was associated with residual disease after immunotherapy, poor response, and adverse outcome. Together, these findings identify the SP-TACR1-SLPI axis as a neural pathway linking cancer stemness to immune escape and nominate this pathway as a target for combination immunotherapy.