J Adv Res. 2026 Apr 5:S2090-1232(26)00280-8. doi: 10.1016/j.jare.2026.04.002. Online ahead of print.

ABSTRACT

INTRODUCTION: The clinical benefit of combining lenvatinib with PD-1 blockade in HCC is frequently constrained by adaptive resistance and the development of an immune-cold tumor microenvironment.

OBJECTIVES: This study aimed to elucidate the molecular mechanisms underlying adaptive resistance and immune exclusion during lenvatinib-PD-1 therapy in HCC, with a particular focus on a UBTF/HSP90A/MIF regulatory circuit. We examined whether genetic or pharmacologic targeting of macrophage migration inhibitory factor (MIF) could restore lenvatinib sensitivity, remodel the tumor immune microenvironment, and serve as a predictive biomarker in clinical cohorts.

METHODS: Paired lenvatinib-sensitive and -resistant HCC models were interrogated using integrated multi-omic and functional approaches, including RNA sequencing, promoter pull-down assays, ChIP, luciferase reporter assays, PLA, and flow cytometry. Key findings were validated in patient-derived organoids and xenografts, as well as in an immunocompetent hydrodynamic HCC mouse model. Clinical relevance was evaluated in independent cohorts treated with lenvatinib plus anti-PD-1 therapy.

RESULTS: UBTF directly bound to and transcriptionally activated the HSP90A promoter, resulting in increased HSP90A expression and stabilization of MIF. MIF signaling through CD74 co-activated the PI3K-AKT and MAPK pathways, sustaining tumor cell proliferation under lenvatinib pressure. Single-cell RNA sequencing and multiplex immunohistochemistry revealed macrophage enrichment and CD8⁺ T-cell exclusion in resistant tumors. Genetic ablation of Mif (Alb-Cre; Mif^flox/flox) or pharmacologic inhibition with 4-IPP (4-Iodo-6-phenylpyrimidine) restored lenvatinib sensitivity, reprogrammed the tumor immune microenvironment, and, when combined with PD-1 blockade, achieved superior tumor control and prolonged survival. In clinical datasets, low pretreatment MIF expression was associated with improved responses to lenvatinib plus PD-1 therapy.

CONCLUSIONS: These findings define a UBTF/HSP90A/MIF axis linking proteostasis and cytokine signaling to immune-metabolic dysfunction and lenvatinib resistance in HCC. MIF emerges as both a mechanistic driver and a predictive biomarker, supporting prospective evaluation of therapeutic strategies combining lenvatinib-PD-1 with MIF- or HSP90A-targeted interventions to personalize TKI-ICI therapy.

PMID:41946392 | DOI:10.1016/j.jare.2026.04.002

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