Targeting Lactate‐Driven Stromal Autophagy via MCT1 Disrupts the Immunosuppressive Niche and Sensitizes Pancreatic Cancer to PD‐1 Blockade

ABSTRACT Lactate reshapes the tumor microenvironment (TME) through complex communication between cancer and stromal cells. However, it remains undefined whether lactate mediates the interaction between pancreatic cancer (PC) cells and pancreatic stellate cells (PSCs), a significant TME component driving tumorigenesis. This study elucidates the metabolic crosstalk between PC cells and PSCs underlying lactate‐driven tumor progression. Our findings demonstrate that PC cells serve as the primary lactate source in the TME, where lactate induces PSC activation through an autophagy‐dependent mechanism mediated by protein lactylation. This activation cascade subsequently upregulates programmed cell death‐1 (PD‐1) expression in CD8 + T cells, promoting immune evasion. Notably, AZD3965, a specific MCT1 inhibitor, sensitizes orthotopic PC to PD‐1 blockade, effectively inhibiting tumor development. Mechanistically, MCT1‐mediated lactate influx activates PSCs by inducing lactylation of lysine residues K356 and K781 on Vps34, a key autophagy regulator. Moreover, activated PSCs secrete CXCL9/CXCL10, which upregulates PD‐1 expression in CD8 + T cells via the CXCR3/STAT3 pathway. This study establishes lactate as a crucial TME signaling molecule orchestrating PSC activation and an immunosuppressive microenvironment, providing compelling evidence for combining MCT1 inhibition with immune checkpoint blockade for pancreatic cancer.