Capsaicin-induced Ca²⁺ overload and ablation of TRPV1-expressing axonal terminals for comfortable tumor immunotherapy

As a common malignancy symptom, cancer pain significantly affects patients’ quality of life. Approximately 60%–90% of patients with advanced cancer experience debilitating pain. Therefore, a comprehensive treatment system that combines cancer pain suppression and tumor treatment could provide significant benefits for these patients. Here, we designed a manganese oxide (MnO₂)/Bovine serum albumin (BSA)/polydopamine (PDA) composite nanoplatform internally loaded with capsaicin for cancer pain suppression and immunotherapy. MBD&C nanoparticles (NPs) can ablate tumor-innervated sensory nerve fibers via Transient receptor potential vanilloid 1 (TRPV1) channels, thereby reducing the pain caused by various inflammatory mediators. The ablation of TRPV1⁺ nerve terminals can also decrease the secretion of calcitonin gene-related peptide (CGRP) and substance P (SP) in sensory nerve fibers, thus reducing the tumor pain and inhibit tumor progression. MBD&C can promote calcium influx by activating overexpressed TRPV1 channels on the tumor membrane surface, thereby achieving cancer immunotherapy induced by endogenous Ca²⁺ overloading. In addition, MnO₂ NPs can alleviate tumor hypoxia and mitigate the immunosuppressive tumor microenvironment (TME). Ultimately, this treatment system with dual capabilities of inhibiting tumor growth and relieving cancer pain makes comfortable tumor therapy feasible and paves the way for the development of patient-centered approaches to cancer treatment in the future.