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We hypothesized that metabolic rewiring orchestrates resistance to lenvatinib and programmed cell death protein 1 (PD-1) blockade.Methods: We established lenvatinib-sensitive\/lenvatinib-resistant (LS\/LR) HCC models and employed multi-omics (proteomics\/RNA-seq), chromatin immunoprecipitation, luciferase, and RNA immunoprecipitation assays to map hexokinase domain containing protein 1 (HKDC1) regulation. Tumor immunity was profiled by scRNA-seq, multiplex fluorescent immunohistochemistry, and flow cytometry. Spermidine (SPD)+lenvatinib efficacy was tested in cell lines and patient-derived organoids\/xenografts. Therapeutic effects were tested in an immunocompetent hydrodynamic HCC model with hepatocyte-specific Hkdc1 deletion and were analyzed a postoperative cohort (n=40) treated with lenvatinib+PD-1.Results: HKDC1, upregulated in LR HCC, was transcriptionally activated by upstream stimulatory factor 1 (USF1) and promoted spermine synthase (SMS)-mediated polyamine rewiring. This impaired CD8&lt;sup&gt;+&lt;\/sup&gt; T-cell metabolism, reversible by HKDC1 knockdown or SPD. SPD synergized with lenvatinib, triggering autophagy and suppressing tumor growth &lt;i&gt;in vitro&lt;\/i&gt; and &lt;i&gt;in vivo&lt;\/i&gt;. High HKDC1 predicted poor response and survival in patients receiving lenvatinib+aPD-1.Conclusions: A USF1\/HKDC1\/SMS axis couples polyamine metabolism to immune dysfunction and lenvatinib resistance. HKDC1 is a predictive biomarker and therapeutic node and supports polyamine-axis modulation to sensitize HCC to lenvatinib plus PD-1 therapy.<\/jats:p>","DOI":"10.3350\/cmh.2025.1269","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T23:30:17Z","timestamp":1773271817000},"page":"1261-1287","update-policy":"https:\/\/doi.org\/10.3350\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["HKDC1-mediated polyamine rewiring drives lenvatinib resistance and immune escape in hepatocellular carcinoma"],"prefix":"10.3350","volume":"32","author":[{"given":"Shiping","family":"Chen","sequence":"first","affiliation":[{"name":"1Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China"},{"name":"2State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biao","family":"Wang","sequence":"additional","affiliation":[{"name":"3Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"3Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Quan","sequence":"additional","affiliation":[{"name":"1Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, China"},{"name":"2State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Shao","sequence":"additional","affiliation":[{"name":"1Liver Cancer 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