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While programmed death ligand 1 (PD-L1) is well characterized as a ligand inhibiting T-cell function, its intrinsic \u2018reverse signaling\u2019 role in regulating tumor metabolism and shaping the immune landscape remains poorly understood. Here, we investigated the metabolic determinants of resistance to anti-programmed cell death protein 1 (anti-PD-1) therapy and the underlying molecular mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Integrated metabolomics and transcriptomics were performed on tumor samples from patients with non-small cell lung cancer and cell lines. Mechanisms were delineated using RNA sequencing, cleavage under targets and tagmentation assays, metabolic flux analysis, and coculture systems. The therapeutic efficacy of targeting metabolic effectors was evaluated in syngeneic mouse models and correlated with immune profiling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified a distinct metabolic signature characterized by aberrant pyruvate accumulation in patients resistant to anti-PD-1 therapy. Mechanistically, we demonstrate that antibody-mediated ligation of PD-L1 triggers an intrinsic endoplasmic reticulum (ER) stress response via the PERK\u2013ATF4\u2013CHOP axis. ATF4 acts as a transcriptional activator that directly upregulates pyruvate dehydrogenase kinase 4 (PDK4) (blocking pyruvate oxidation) and glutaminase (GLS) (promoting glutaminolysis), creating a \u2018dual-hit\u2019 metabolic rewiring that drives intracellular pyruvate build-up. Subsequently, tumor-secreted pyruvate is taken up by tumor-associated macrophages (TAMs) via MCT1, inducing mitochondrial reactive oxygen species accumulation and driving them into a state of cellular senescence. These senescent TAMs upregulate PD-L1 via STAT3 signaling, thereby reinforcing an immunosuppressive feedback loop. Pharmacological inhibition of PDK4 and GLS effectively abolished pyruvate accumulation, prevented macrophage senescence, and restored CD8+ T-cell cytotoxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study identifies a novel \u2018PD-L1\u2013ER stress\u2013pyruvate\u2013macrophage senescence\u2019 axis as a key mechanism underlying primary resistance to ICB. These findings highlight the non-canonical reverse-signaling function of PD-L1 in metabolic remodeling and propose that targeting the PDK4\/GLS-dependent pyruvate surge offers a promising therapeutic strategy to sensitize tumors to anti-PD-1 immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015037","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:05:12Z","timestamp":1788361512000},"page":"e015037","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the PD-L1-induced PDK4\/GLS metabolic axis overcomes anti-PD-1 resistance in non-small cell lung cancer"],"prefix":"10.1136","volume":"14","author":[{"given":"Wenxin","family":"Lian","sequence":"first","affiliation":[{"name":"Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, 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