Linoleic Acid Potentiates Response to Chemotherapy in Biliary Tract Cancer Through RARγ Activation

ABSTRACT Biliary tract cancer (BTC) remains highly challenging owing to its poor prognosis. Although gemcitabine plus cisplatin (Gem/Cis) represents a standard chemotherapy option, treatment resistance significantly limits the outcomes. Metabolic reprogramming influences therapeutic response; however, the specific metabolic determinants of chemosensitivity in BTC are poorly defined. Using untargeted metabolomics followed by targeted validation, we found that plasma linoleic acid (LA) levels were significantly elevated in patients with chemotherapy‐responsive BTC. LA supplementation led to tumor accumulation and synergistically enhanced Gem/Cis‐induced cytotoxicity in vitro and in vivo. Mechanistic investigations revealed that LA activated retinoic acid receptor gamma (RARγ), and pharmacological or genetic ablation of RARγ abolished the chemosensitizing effects of LA, establishing RARγ as an important mediator. Activation of the LA‐RARγ axis orchestrated a dual proapoptotic and pro‐immune transcriptional program. This resulted in increased cancer cell apoptosis and a remodeled immune microenvironment, characterized by reduced PD‐L1 expression and enhanced CD8 + T cell activation. Taken together, this study identified LA as a novel metabolic modulator that potentiates chemotherapy response in BTC through RARγ activation, orchestrating a dual antitumor response by promoting cancer cell apoptosis and enhancing antitumor immunity.