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TRIM21-mediated degradation of HILPDA overcomes anti-PD-1 immunotherapy resistance in breast cancer by limiting PD-L1 palmitoylation
Oncogene, Published online: 24 March 2026; doi:10.1038/s41388-026-03728-6
TRIM21-mediated degradation of HILPDA overcomes anti-PD-1 immunotherapy resistance in breast cancer by limiting PD-L1 palmitoylationComputational analysis of multi-omics data reveals CXCL10(+) DC-Treg interaction drives immunosuppressive microenvironment in AFP-positive hepatocellular carcinoma
Cell Mol Life Sci. 2026 Mar 19. doi: 10.1007/s00018-026-06167-4. Online ahead of print.
NO ABSTRACT
PMID:41854876 | DOI:10.1007/s00018-026-06167-4
OpenSage: Self-programming Agent Generation Engine
HKDC1-Mediated Polyamine Rewiring Drives Lenvatinib Resistance and Immune Escape in Hepatocellular Carcinoma
Clin Mol Hepatol. 2026 Mar 11. doi: 10.3350/cmh.2025.1269. Online ahead of print.
ABSTRACT
BACKGROUND/AIMS: Lenvatinib resistance and immune exclusion limit outcomes in HCC. We hypothesized that metabolic rewiring orchestrates resistance to lenvatinib and PD-1 blockade.
METHODS: We established LS/LR HCC models and employed multi-omics (proteomics/RNA-seq), ChIP, luciferase, and RIP assays to map HKDC1 regulation. Tumor immunity was profiled by scRNA-seq, mIHC, and flow cytometry. SPD + lenvatinib efficacy was tested in cell lines, patient-derived organoids/xenografts. Tested therapy effect in an immunocompetent hydrodynamic HCC model with hepatocyte-specific Hkdc1 deletion; and analyzed a postoperative cohort (n = 40) treated with lenvatinib + PD-1.
RESULTS: HKDC1, upregulated in LR HCC, was transcriptionally activated by USF1 and promoted SMS-mediated polyamine rewiring. This impaired CD8⁺ T-cell metabolism, reversible by HKDC1 knockdown or spermidine (SPD). SPD synergized with lenvatinib, triggering autophagy and suppressing tumor growth in vitro and in vivo. 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 support polyamine-axis modulation to sensitize HCC to lenvatinib plus PD-1 therapy.
PMID:41812646 | DOI:10.3350/cmh.2025.1269