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LDHA-driven lactate metabolism promotes MDSC activation and immunosuppressive microenvironment in prostate cancer
Xiyi Wei1,2, Xiao Li1, Yitong Pan3
1Department of Urology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing, China.
Abstract:
Immunotherapy has achieved limited efficacy in prostate cancer (PCa), largely due to its profoundly immunosuppressive tumor microenvironment (TME). However, the metabolic mechanisms underpinning this immune resistance remain poorly defined. Here, we identify lactate dehydrogenase A (LDHA)-driven lactate metabolism as a critical regulator of myeloid-derived suppressor cell (MDSC) activation in PCa. Integrated metabolomic, single-cell, and spatial transcriptomic analyses revealed that LDHA is highly expressed in PCa malignant epithelial cells and correlates with increased lactate production and immune exclusion. LDHA-high tumors exhibited enriched infiltration of polymorphonuclear MDSCs (PMN-MDSCs), which were spatially co-localized with LDHA-positive tumor regions. Mechanistically, lactate uptake through monocarboxylate transporter 1 (MCT1) enhanced PMN-MDSC differentiation and upregulated Arg1 and NOS2, reinforcing T cell suppression. Genetic ablation of LDHA in murine models markedly reduced PMN-MDSC infiltration, restored CD8+T cell activity, and inhibited tumor growth. Pharmacological inhibition of LDHA with FX-11 synergized with anti-PD-L1 therapy, producing durable tumor regression. Collectively, these findings define LDHA-driven lactate metabolism as a key metabolic checkpoint in PCa immune evasion and provide a rationale for combining LDHA inhibition with immune checkpoint blockade to overcome immunotherapy resistance.
Insights
Lactate dehydrogenase A (LDHA) fuels immunosuppression in prostate cancer (PCa) by activating myeloid-derived suppressor cells (MDSCs). Inhibiting LDHA can restore anti-tumor immunity and enhance immunotherapy effectiveness in PCa.
Area of Science:
- Oncology
- Immunology
- Metabolic pathways
Background:
- Prostate cancer (PCa) immunotherapy efficacy is limited by an immunosuppressive tumor microenvironment (TME).
- Metabolic drivers of immune resistance in PCa's TME are not well understood.
- Myeloid-derived suppressor cells (MDSCs) contribute significantly to immune suppression in PCa.
Purpose of the Study:
- To investigate the role of lactate dehydrogenase A (LDHA) and lactate metabolism in regulating MDSC activation within the PCa TME.
- To explore LDHA as a potential therapeutic target to overcome immune resistance in prostate cancer.
Main Methods:
- Integrated analysis of metabolomics, single-cell, and spatial transcriptomics in PCa.
- Assessment of LDHA expression in PCa cells and its correlation with MDSC infiltration.
- Murine models for genetic ablation of LDHA and combination therapy studies (LDHA inhibition with anti-PD-L1).
Main Results:
- LDHA is highly expressed in PCa epithelial cells, correlating with increased lactate production and immune exclusion.
- LDHA-high tumors show increased infiltration of polymorphonuclear MDSCs (PMN-MDSCs), co-localized with LDHA-positive regions.
- Lactate uptake via MCT1 promotes PMN-MDSC differentiation and T cell suppression.
- LDHA genetic ablation reduced PMN-MDSCs, enhanced CD8+ T cell activity, and inhibited tumor growth in mice.
- Pharmacological LDHA inhibition (FX-11) combined with anti-PD-L1 therapy led to durable tumor regression.
Conclusions:
- LDHA-driven lactate metabolism is a critical regulator of MDSC activation and immune suppression in prostate cancer.
- Targeting LDHA represents a promising strategy to enhance immunotherapy response in PCa by modulating the TME.
- Combining LDHA inhibitors with immune checkpoint inhibitors may overcome immunotherapy resistance in prostate cancer.
