Lysophosphatidylcholine (LPC 18:2) Reprograms the Tumor Immune Microenvironment to Potentiate Immune Checkpoint Blockade 2309882

Abstract Introduction Lysophosphatidylcholine (LPC) is a bioactive lipid with emerging immunomodulatory properties, but its potential as an adjuvant to immune checkpoint blockade (ICB) is poorly understood. We hypothesized that LPC could reprogram the tumor microenvironment to boost the efficacy of anti—PD-1/anti—CTLA-4 therapy. Methods Using syngeneic mouse models of MCA205 fibrosarcoma, MC38 colon adenocarcinoma, and CMT167 lung carcinoma, tumors were established bilaterally and treated with IgG control, ICB (anti—PD-1 + anti—CTLA-4), or ICB plus LPC18:2. Tumor growth, survival, serum cytokines, flow cytometry, and bulk RNA-seq were used to characterize treatment responses. Results Across models, ICB + LPC consistently reduced tumor growth compared with ICB alone, with an increased fraction of long-term responders. Bulk RNA-seq of MC38 tumors revealed that ICB alone modestly induced interferon response and antigen-presentation pathways, while addition of LPC produced a much stronger and more coherent transcriptional program. Gene-set and GO enrichment analyses showed marked up-regulation of adaptive immunity, T-cell cytotoxicity, and both MHC class I and II antigen-processing pathways, alongside interferon-stimulated IRG/GBP modules and DNA-sensing genes. Jaccard similarity analysis demonstrated that LPC specifically amplifies and consolidates these immune modules rather than introducing unrelated pathways. Conclusion Together, these data support a model in which LPC enhances ICB by reprogramming myeloid and antigen-presenting cell compartments to drive stronger interferon signaling and T-cell effector function. Ongoing 10x Genomics 3’ scRNA-seq of CD45+ tumor-infiltrating cells will define the precise cellular states and circuits engaged by LPC in combination with checkpoint blockade. Funding Source NIH R01 CA256133(2007105000403) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)