The Role of SRSF10 in Immunotherapy for Hepatocellular Carcinoma

Academic Background

Hepatocellular carcinoma (HCC) ranks sixth in global cancer incidence and third in mortality. Although surgical resection is the primary treatment for HCC, the high postoperative recurrence rate significantly impacts patient prognosis. In recent years, immunotherapy has shown remarkable efficacy in various cancer types, particularly achieving breakthroughs in melanoma and lung cancer. However, the response rate of HCC patients to immune checkpoint blockade therapy (e.g., PD-1/PD-L1 antibodies) is less than 30%, with no significant improvement in overall survival. This limitation is primarily attributed to the heterogeneity and immunosuppressive nature of the tumor microenvironment (TME).

Macrophages in the TME play a crucial role in the immunosuppression of HCC. Macrophages exhibit high plasticity and can be classified into pro-inflammatory M1-type and anti-inflammatory M2-type. M2-type macrophages promote tumor immune evasion and angiogenesis by secreting immunosuppressive factors such as IL-10 and TGF-β1. Therefore, regulating the polarization state of macrophages, especially converting M2-type macrophages to M1-type, has become a key strategy to enhance the efficacy of immunotherapy in HCC.

Additionally, metabolic reprogramming in tumor cells (e.g., enhanced glycolysis) is also believed to play a significant role in immune evasion. The byproduct of glycolysis, lactate, not only inhibits the activity of CD8+ T cells but also promotes the formation of an immunosuppressive microenvironment through various mechanisms. However, the exact mechanisms by which glycolysis directly leads to immune evasion remain unclear.

Source of the Paper

This paper was authored by Jialiang Cai, Lina Song, Feng Zhang, and others from the Liver Cancer Institute of Zhongshan Hospital, Fudan University, and published on August 21, 2024, in the journal Cancer Communications. The study was supported by the National Natural Science Foundation of China and the Shanghai Municipal Science and Technology Commission.

Research Process and Results

1. Research Objectives and Screening of Key Genes

The research team first identified key genes associated with immunotherapy resistance through single-nuclear RNA sequencing (snRNA-seq), multiplex immunofluorescence, and analysis of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The study found that serine/arginine-rich splicing factor 10 (SRSF10) is highly expressed in various tumors and associated with poor prognosis. Further analysis revealed that SRSF10 is closely related to the glycolysis pathway, suggesting its potential role in tumor metabolic reprogramming and immune evasion.

2. The Role of SRSF10 in the Tumor Microenvironment

To validate the function of SRSF10, the research team constructed SRSF10-knockdown HCC cell lines and conducted in vivo experiments using mouse models. The results showed that SRSF10 knockdown significantly inhibited HCC tumor growth and altered the composition of the TME. Specifically, after SRSF10 knockdown, the proportion of CD8+ T cells in the TME significantly increased, while the proportion of M2-type macrophages decreased. These results indicate that SRSF10 influences tumor immune evasion by regulating macrophage polarization.

3. SRSF10 Regulates Macrophage Polarization via Lactate

Further research revealed that SRSF10 promotes lactate production by regulating the glycolysis pathway. Lactate, a byproduct of glycolysis, induces M2 macrophage polarization through histone lactylation. The specific mechanism involves SRSF10 binding to the 3’ untranslated region (3’UTR) of MYB mRNA, enhancing MYB RNA stability, and subsequently upregulating the expression of key glycolysis enzymes (e.g., GLUT1, HK1, and LDHA), leading to increased intracellular and extracellular lactate levels. Lactate accumulation further induces histone lactylation, thereby promoting M2 macrophage polarization.

4. The Relationship Between SRSF10 and Immunotherapy Resistance

Clinical data analysis showed that HCC patients with high SRSF10 expression had a lower response rate to PD-1 antibody therapy. The research team further validated the efficacy of the SRSF10 inhibitor 1C8 using mouse models. The results demonstrated that 1C8 significantly enhanced the therapeutic effect of PD-1 antibodies, suggesting that inhibiting SRSF10 may overcome resistance to PD-1 therapy in HCC.

Conclusions and Significance

This study revealed the critical role of SRSF10 in HCC immune evasion and elucidated its molecular mechanism of influencing macrophage polarization through the regulation of glycolysis and lactate metabolism. The findings indicate that SRSF10 is not only a potential biomarker for immunotherapy resistance in HCC but also provides a new therapeutic target. By inhibiting SRSF10, the immunosuppressive state of the TME can be reversed, enhancing the efficacy of PD-1 antibodies.

Research Highlights

1. Innovative Discovery: This study is the first to reveal that SRSF10 regulates macrophage polarization through glycolysis and lactate metabolism, providing new insights for HCC immunotherapy.
2. Multidimensional Validation: The research combined single-nuclear RNA sequencing, multiplex immunofluorescence, mouse models, and clinical sample analysis to comprehensively validate the function of SRSF10 and its role in immunotherapy resistance.
3. Clinical Application Potential: The discovery of the SRSF10 inhibitor 1C8 provides a new drug target for HCC immunotherapy, with significant clinical application value.

Additional Valuable Information

The study also developed a patient-derived organotypic tumor spheroid (PDOTs) model to evaluate the combined therapeutic effect of the SRSF10 inhibitor and PD-1 antibodies. This model provides an important experimental platform for personalized HCC treatment in the future.

This research not only deepens our understanding of the mechanisms of immune evasion in HCC but also provides important theoretical and experimental support for the development of new immunotherapy strategies.