GPR162 Drives Obesity-Associated Lung Adenocarcinoma Suppression via Fatty Acid Oxidation-Induced Cuproptosis and Metabolic-Immune Reprogramming

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Abstract
Obesity, a well-established risk factor for cancer development and progression, exerts its oncogenic effects primarily through metabolic reprogramming, particularly in lipid and amino acid metabolism. Despite its clinical significance, the molecular mechanisms linking obesity-induced metabolic alterations to lung adenocarcinoma progression remain elusive. In this study, we identify G protein-coupled receptor 162 (GPR162) as a pivotal metabolic-immune regulator in obesity-associated lung adenocarcinoma. Our findings reveal that GPR162 orchestrates tumor suppression through two distinct yet interconnected mechanisms: (1) GPR162 induces cell peroxidation by promoting the oxidation of medium-chain fatty acids such as decanoic acid and lauric acid. (2) GPR162 interacts with copper transporter SLC25A3 to form a functional complex in the mitochondria, driving copper influx and further promoting intracellular lipid peroxidation to induce cuproptosis, which directly kills tumor cells. The synergistic effect of fatty acid oxidation and cuproptosis not only reprogram the tumor metabolic microenvironment, but also induce the polarization of tumor-associated macrophages to M1 type, enhance CD8 + T cell infiltration and IFNγ secretion, and finally construct an immune microenvironment that inhibits tumor progression. This study provides a new target and theoretical basis for combined metabolic-immune treatment of obesity-related lung cancer.

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