was found to be upregulated in various tumors and is associated with poor prognosis.
SRSF10 positively regulates lactate production, creating a feedback loop that enhances its own expression.
Elevated lactate levels promote the polarization of , which inhibit CD8T cell activity.
SRSF10 interacts with MYB, increasing its RNA stability and upregulating -related enzymes.
The accumulation of lactate in tumors contributes to an immunosuppressive tumor microenvironment by activating pro-tumor macrophages.
SRSF10 may serve as a biomarker for assessing immunotherapy resistance in various solid tumors.
Targeting SRSF10 with inhibitor 1C8 has the potential to improve the effectiveness of PD-1 monoclonal antibodies in treatment.
Simplified
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 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// histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8T 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. , in turn, inhibited the enrichment of CD8T cells and the proportion of interferon-γCD8T 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.
Key numbers
15 mg/kg
Tumor growth reduction
Dose of 1C8 administered to inhibit in mice.
less than 30%
Response rate to anti-PD-1 therapy
Percentage of patients responding to PD-1 blockade in HCC.
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