An Iridium(III) Complex Induces Immunogenic Methuosis and Reprograms Tumor-Associated Macrophages for Chemoimmunotherapy against KRAS-Mutated Tumors

Effective chemoimmunotherapy necessitates strategies capable of concurrently eliminating malignant cells and reprogramming the immunosuppressive tumor microenvironment. However, therapeutic outcomes are often compromised by tumor-associated macrophages (TAMs), and existing nanomedicine-based cotargeting approaches encounter considerable translational challenges. Here, we report Ir-estin, an iridium(III) complex that selectively triggers methuosis, a form of macropinocytosis-associated cell death, in KRAS-mutated tumor cells while sparing KRAS-WT and noncancerous cells. We establish that Ir-estin -induced methuosis is immunogenic. Importantly, Ir-estin also stimulates noncytotoxic, AMPK-dependent macropinocytosis in macrophages, a process associated with M1 polarization of TAMs and innate immune activation. This dual mechanism enables synchronized engagement of innate and adaptive anticancer immune responses, leading to potent chemoimmunotherapy in vivo. To the best of our knowledge, Ir-estin represents the first metal-based therapeutic agent to couple immunogenic methuosis with AMPK-dependent macrophage macropinocytosis and TAM reprogramming within a single small-molecule entity.