Targeting the noncanonical function of metabolic enzyme PHGDH in driving PD-L1 expression and cancer immune evasion.

Phosphoglycerate dehydrogenase (PHGDH), a rate-limiting enzyme in serine synthesis, is frequently overexpressed in cancers and promotes cancer progression. Its oncogenic role has been largely attributed to its enzymatic activity. Here, we uncover a critical noncanonical function of PHGDH in cancer; PHGDH upregulates PD-L1 expression to promote cancer immune evasion independently of its enzymatic function. Mechanistically, PHGDH binds to the serine/threonine kinase RAF1 and disrupts its interaction with 14-3-3, thereby activating RAF1 and its downstream MEK/ERK signaling to induce PD-L1 expression. Elevated PHGDH levels correlate with increased PD-L1 expression in clinical tumor samples. In preclinical mouse models, tumors with high PHGDH expression exhibit increased sensitivity to PD-1/PD-L1 blockade. Combining PHGDH inhibitors with PD-1/PD-L1 blockade significantly improves antitumor effects compared to individual treatments. These results identify PHGDH as an important PD-L1 regulator, reveal a critical noncanonical mechanism underlying PHGDH's oncogenic function, and propose a potential therapeutic strategy for cancers with PHGDH overexpression.