Nanoparticles-mediated TRPV1 channel blockade amplifies cancer thermo-immunotherapy via heat shock factor 1 modulation

Survival of malignant tumours is highly relevant to their intrinsic self-defense pathways such as heat shock protein (HSP) during cancer therapy, yet precisely dismantling self-defenses to amplify antitumour potency remains unexplored. Herein, we demonstrate that nanoparticles-mediated transient receptor potential vanilloid member 1 (TRPV1) channel blockade selectively modulates heat shock factor 1 to suppress dual self-defense pathways for potentiating thermo-immunotherapy. TRPV1 blockade is identified to inhibit calcium influx and subsequent nuclear translocation of HSF1 upon hyperthermia, leading to selective suppression of stressfully overexpressed HSP70 for enhancing thermotherapeutic efficacy against a variety of primary, metastatic and recurrent tumours. Particularly, the suppression of HSF1 translocation further restrains TGF pathway to apparently degrade extracellular matrix in tumour for improving the infiltration of antitumour therapeutics and immune cells into highly fibrotic and immunosuppressive pancreatic cancers, ultimately synergizing with anti-PD-L1 antibody to retrieve thermo-immunotherapy with tumour-eradicable and immune memory effects. The nanoparticles-mediated TRPV1 blockade represents as an effective and universal approach to selectively dismantle self-defenses for potent cancer therapy.