Targeting SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular
Jialiang Cai1,2,3, Lina Song1,2,3, Feng Zhang4,5
1Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.
Background:
The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine- and arginine-rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy.
Methods:
To identify the key genes associated with immunotherapy resistance, we conducted single-nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems, flow cytometry, various tumor-bearing mouse models, and patient-derived organotypic tumor spheroids.
Results:
SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8+ T cell activity. Mechanistically, SRSF10 interacted with the 3'-untranslated region of MYB, enhancing MYB RNA stability, and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1 (GLUT1), hexokinase 1 (HK1), lactate dehydrogenase A (LDHA), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro-tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8+ T cells and the proportion of interferon-γ+CD8+ T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) in both murine and human preclinical models.
Conclusions:
The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.
Insights
SRSF10 promotes immune evasion in hepatocellular carcinoma by regulating lactate production and macrophage polarization. Targeting SRSF10 with 1C8 enhances anti-PD-1 therapy efficacy, offering a new strategy for cancer treatment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint blockade therapy shows limited efficacy in hepatocellular carcinoma (HCC).
- The role of serine- and arginine-rich splicing factor (SRSF) family members in tumor immunology is not well understood.
- SRSF10's specific function in HCC immunotherapy warrants investigation.
Purpose of the Study:
- To investigate the role of SRSF10 in immune evasion within the tumor microenvironment (TME) of HCC.
- To elucidate the molecular mechanisms by which SRSF10 contributes to immunotherapy resistance.
- To evaluate SRSF10 as a potential biomarker and therapeutic target for HCC immunotherapy.
Main Methods:
- Single-nuclear RNA sequencing and database analyses (TCGA, GEO) identified key genes in immunotherapy resistance.
- In vitro co-culture systems, flow cytometry, and mouse models assessed SRSF10's function in immune evasion.
- Patient-derived organotypic tumor spheroids were used to validate findings in a more complex model.
Main Results:
- SRSF10 upregulation correlates with poor prognosis and increased lactate production via the SRSF10/MYB/glycolysis axis.
- Elevated lactate promotes M2 macrophage polarization, suppressing CD8+ T cell activity and creating an immunosuppressive TME.
- SRSF10 acts as a biomarker for immunotherapy resistance, and its inhibition (1C8) enhances anti-PD-1 efficacy in preclinical models.
Conclusions:
- The SRSF10/MYB/glycolysis/lactate pathway is crucial for immune evasion and resistance to anti-PD-1 therapy.
- Targeting SRSF10 with 1C8 demonstrates potential to overcome anti-PD-1 tolerance in HCC.
- SRSF10 inhibition represents a promising strategy to improve immunotherapy outcomes in hepatocellular carcinoma.
