2026-04-01 ラトガース大学
＜関連情報＞
- https://www.rutgers.edu/news/common-metabolic-enzyme-could-predict-cancer-immunotherapy-benefits-and-help-more-patients
- https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(26)00121-7
PD-L1発現および癌免疫回避を促進する代謝酵素PHGDHの非定型的機能を標的とする Targeting the noncanonical function of metabolic enzyme PHGDH in driving PD-L1 expression and cancer immune evasion
Juan Liu ∙ Weiwei Wang ∙ Yvonne Sun ∙ … ∙ Haiyan Zheng ∙ Wenwei Hu ∙ Zhaohui Feng
Cell Reports Medicine Published:March 28, 2026
DOI:https://doi.org/10.1016/j.xcrm.2026.102704
Graphical abstract
Highlights
- PHGDH drives PD-L1 expression and immune evasion independently of its enzymatic activity
- PHGDH binds to RAF1 and activates RAF1-MEK/ERK pathway to drive PD-L1 expression
- Cancers with PHGDH overexpression exhibit increased sensitivity to PD-1/PD-L1 blockade
- Combining PHGDH inhibitors with PD-1/PD-L1 blockade improves antitumor effects
Summary
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.
