二甲双胍通过AMPK-KLF4-TFRC介导的M2型巨噬细胞铁死亡机制，增强肺腺癌免疫化疗疗效。

Abstract

Metformin has been clinically observed to improve outcomes when combined with immunochemotherapy in non-small cell lung cancer, yet the underlying sensitization mechanisms remain poorly understood. By bridging clinical observations with mechanistic insights, multiplex immunofluorescence analysis of lung adenocarcinoma specimens revealed that metformin use was associated with heightened lipid peroxidation specifically within intratumoral M2 macrophages, leading to a significant reduction in M2 density. In both THP-1 and human peripheral blood mononuclear cell-derived models, metformin selectively sensitized M2, but not M1, macrophages to ferroptosis, and this effect was reversed by ferroptosis inhibitors or TFRC blockade. Mechanistically, we identified KLF4 as a key transcriptional driver of TFRC, which is more abundantly expressed in M2 macrophages. Metformin triggers AMPK activation, leading to KLF4 phosphorylation (at Ser236) and its subsequent nuclear accumulation to promote TFRC transcription. Functionally, macrophage depletion in syngeneic mouse models abrogated the therapeutic benefit of metformin, demonstrating that its synergy with immunochemotherapy is mediated by intratumoral macrophages. Collectively, our findings define an AMPK–KLF4–TFRC axis that selectively triggers M2 macrophage ferroptosis, thereby remodeling the immune microenvironment to potentiate immunochemotherapy in lung adenocarcinoma.