Resistance to immune checkpoint blockade (ICB) therapy remains a major obstacle to successful cancer treatment and represents a significant unmet clinical need. Identifying clinically actionable targets to overcome this resistance is therefore essential for developing effective combination strategies with ICB. In this study, using transcriptomic data from cancer patients treated with programmed cell death protein 1 (PD-1) therapy and established mouse preclinical PD-1 blockade-resistant models, we identify transient receptor potential vanilloid 1 (TRPV1) as a crucial mediator that enables tumor cells to resist cytotoxic T lymphocyte (CTL)-mediated killing, thereby facilitating immune escape from PD-1 therapy. Mechanically, TRPV1 enhances autophagy-dependent secretion of epidermal growth factor (EGF), which in turn activates epidermal growth factor receptor (EGFR) signaling, ultimately leading to tumor cell resistance to CTL-mediated cytotoxicity. Importantly, pharmacological inhibition of TRPV1 sensitizes resistant tumors to PD-1 blockade by restoring anti-tumor immune response. Thus, our findings highlight TRPV1 as a promising therapeutic target for overcoming resistance to PD-1 blockade and provide a strong rationale for combining TRPV1 antagonists with anti-PD-1 therapy.