Dual-targeting evodiamine analogue overcomes pancreatic cancer immunotherapy resistance by inducing immunogenic cell death.

Pancreatic cancer treatment is severely hampered by poor drug delivery through its dense stromal barrier and an immunosuppressive tumor microenvironment, which together contribute to resistance to immune checkpoint blockade. To address these two major obstacles, we rationally designed and synthesized a novel conjugate, termed EVO-FAPI. This molecule covalently links a 3-fluoro-10-hydroxyl-evodiamine (EVO) derivative, a potent cytotoxic alkaloid and inducer of immunogenic cell death (ICD), to a fibroblast activation protein inhibitor (FAPI) that selectively targets fibroblast activation protein alpha (FAPα)-expressing stromal fibroblasts abundant in pancreatic tumors. By selectively inducing ICD in both cancer cells and the tumor stroma, EVO‑FAPI promotes ICD‑mediated activation of the anti‑tumor immune response. Importantly, when combined with α-PD-1, EVO-FAPI increased the tumor growth inhibition rate from 35% to 67%, markedly improving therapeutic efficacy compared with α-PD-1 monotherapy. Collectively, these findings identify EVO-FAPI as a rationally engineered dual-function agent that integrates targeted stromal modulation with immunotherapy sensitization, thereby overcoming resistance to immune checkpoint blockade in pancreatic cancer.