Clinical and Molecular Hepatology | HKDC1-Mediated Polyamine Metabolic Reprogramming Drives Lenvatinib Resistance and Immune Escape in Hepatocellular Carcinoma

This study reveals the dual regulatory role of HKDC1 in therapy resistance and immune suppression in liver cancer, providing a critical theoretical foundation for designing combination therapeutic strategies targeting metabolic-immune crosstalk.

 

Literature Overview

The article titled 'HKDC1-mediated polyamine rewiring drives lenvatinib resistance and immune escape in hepatocellular carcinoma,' published in the journal Clinical and Molecular Hepatology, systematically investigates the metabolic mechanisms underlying lenvatinib resistance and immune escape in hepatocellular carcinoma (HCC). Through integrated multi-omics analyses, the study identifies HKDC1 as a key molecule associated with drug resistance and deeply elucidates its mechanism of shaping the tumor microenvironment via regulation of polyamine metabolism. This work not only redefines the resistant phenotype as one co-characterized by metabolic buffering and immune suppression but also offers novel insights into overcoming dual resistance to targeted and immunotherapies.

Background Knowledge

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide, with most patients diagnosed at intermediate or advanced stages, making systemic therapy the primary treatment option. Although the combination of lenvatinib and PD-1 inhibitors has significantly improved outcomes for some patients, primary or acquired resistance remains common, leading to treatment failure. Currently, HKDC1 research has primarily focused on glucose and lipid metabolism regulation and tumor progression, but its role in resistance to targeted therapy remains unclear. In particular, in HCC, whether a central node coordinates metabolic reprogramming and immune microenvironment remodeling remains a critical unresolved bottleneck. This study addresses this gap by systematically exploring the crosstalk between metabolism and immunity based on clinical observations of resistance, ultimately identifying the HKDC1-polyamine axis as a common driver of resistance and immune escape. By integrating transcriptomic, proteomic, and chromatin immunoprecipitation data, the authors establish the USF1→HKDC1→SMS regulatory pathway, highlighting its central role in HCC treatment resistance.

 

 

Research Methods and Experiments

The authors first established lenvatinib-sensitive (LS) and lenvatinib-resistant (LR) HCC cell line models, validating the resistant phenotype using CCK-8, colony formation, and mouse xenograft experiments. Proteomic screening identified HKDC1 as significantly upregulated in LR cells. Subsequent validation using qRT-PCR, Western blot, and immunohistochemistry across multiple cell lines and clinical samples confirmed the expression pattern of HKDC1 and its association with patient prognosis. To investigate the underlying mechanism, the authors employed shRNA to knock down [[HKDC1]], followed by RNA-seq and metabolomic analyses, which revealed a significant impact on polyamine metabolism, particularly SMS expression. RNA immunoprecipitation (RIP) and dual-luciferase promoter reporter assays confirmed that HKDC1 binds to SMS mRNA and enhances its stability, while USF1 directly activates HKDC1 transcription by binding to its promoter region. Furthermore, patient-derived organoids (PDOs) and PDX models were used to validate the synergistic anti-tumor effects of SPD combined with lenvatinib.

Key Conclusions and Perspectives

• In LR-HCC, upregulation of USF1 activates [[HKDC1]] transcription, which in turn enhances SMS mRNA stability, promotes spermine synthesis, depletes SPD, and leads to polyamine metabolic imbalance. This finding suggests that targeting the USF1/HKDC1/SMS axis may reverse the resistant phenotype, providing molecular targets for novel metabolic intervention strategies.
• Elevated HKDC1 expression depletes SPD in the microenvironment, suppressing mitochondrial respiration and effector functions of CD8+ T cells, thereby driving T cell exhaustion and tumor immune escape. This indicates that HKDC1 is not only a cell-autonomous resistance factor in tumor cells but also a key hub regulating the tumor immune microenvironment (TIME), suggesting its potential as a biomarker to predict response to immunotherapy.
• Exogenous supplementation of SPD restores autophagic cell death induced by lenvatinib, significantly enhancing drug sensitivity in LR cells and achieving tumor control in PDX models. These results support SPD as a potential sensitizer in combination therapy and suggest clinical feasibility of combining polyamine metabolic modulators with targeted or immunotherapies.
• Clinical cohort analysis shows that patients with high HKDC1 expression have lower response rates to lenvatinib plus aPD-1 therapy and shorter progression-free survival (PFS), confirming its clinical value as a predictive biomarker. This provides a new stratification tool for precision therapy in HCC, helping to identify patient populations who may benefit from HKDC1 inhibition.

Research Significance and Prospects

This study redefines HCC resistance mechanisms from a metabolic perspective, establishing the HKDC1-polyamine axis as a 'metabolic checkpoint' linking intrinsic tumor cell resistance and extrinsic immune suppression. From a drug development standpoint, small-molecule inhibitors targeting HKDC1 or SMS, or nutritional interventions involving exogenous SPD supplementation, represent promising new directions for overcoming resistance to combination therapies. In clinical monitoring, assessing HKDC1 expression levels in tumor tissues or liquid biopsies may help identify patients at high risk of resistance early, enabling personalized treatment adjustments. Moreover, this mechanism underscores the central role of metabolic reprogramming in immunotherapy resistance, prompting future exploration of whether other metabolic nodes participate in similar regulation, thereby expanding the spectrum of combination therapy targets.

 

 

Conclusion

This study systematically reveals the critical role of HKDC1-mediated polyamine metabolic reprogramming in hepatocellular carcinoma resistance and immune escape. By establishing the USF1→HKDC1→SMS regulatory axis, the authors elucidate how tumor cells achieve tolerance to lenvatinib through metabolic 'buffering' while simultaneously shaping an immunosuppressive microenvironment to evade immune clearance. This dual mechanism provides new intervention nodes for HCC therapy. Exogenous SPD supplementation not only restores drug sensitivity but also partially reverses T cell exhaustion, demonstrating the immense potential of metabolic interventions in sensitizing tumors to combined targeted and immunotherapies. From bench to bedside, this discovery lays the theoretical foundation for developing stratified treatment strategies based on HKDC1 status, suggesting that future treatment selection could be guided by HKDC1 expression and that polyamine metabolic modulators may serve as novel sensitizing agents, potentially significantly improving long-term survival in HCC patients. This work marks a paradigm shift from 'single-target' to 'metabolic-immune network' interventions and represents a significant step forward in advancing precision therapy for HCC.

 

Shiping Chen, Biao Wang, Yang Zhang, Yufan Cai, and Zhi Dai. HKDC1-mediated polyamine rewiring drives lenvatinib resistance and immune escape in hepatocellular carcinoma. Clinical and Molecular Hepatology.