Abstract Background: The sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling axis regulates tumor progression and immune suppression within the tumor microenvironment (TME). While SPHK1-mediated S1P generation is known to promote ovarian cancer growth, its role in shaping B cell-driven anti-tumor immunity remains unclear. Methods and Results: Genetic ablation of SPHK1 (SPHK1-/-) in murine ovarian cancer (ID8 Trp53-/-; Brca2-/-), melanoma (B16F10), and colorectal cancer (MC38) models resulted in markedly reduced tumor burden accompanied by ∼50% reduction in S1P levels. Tumors from SPHK1-/- mice demonstrated increased immune infiltration, primarily B and T lymphocytes, and enrichment of immunoglobulin-related and antigen presentation gene signatures. Flow cytometry and IHC confirmed enhanced tumor-infiltrating CD19+ B cells, plasma cells, and upregulation of activation and antigen-presentation markers (CD69, CD80, CD86, CD40, MHC-II).Mechanistically, SPHK1 deficiency promoted metabolic reprogramming that supported plasma cell differentiation, characterized by elevated unfolded protein response (XBP1, BiP, GRP94), increased oxidative phosphorylation, ATP generation, mitochondrial biogenesis, and FOXO1 activation. Pharmacologic SPHK1 inhibition using PF543 phenocopied genetic knockout, increasing plasma cell frequency, immunoglobulin secretion, and activation-associated transcriptional programs. Taken together, our data suggest that SPHK1 inhibition activates B cells for enhanced anti- tumor immune response. Conclusion: SPHK1/S1P axis inhibition reprograms B cells toward robust metabolic fitness, plasma cell differentiation, and antibody-mediated anti-tumor immunity. Targeting SPHK1 represents a promising strategy to boost humoral immunity and overcome immune-excluded ovarian cancer phenotypes. Impact: This study uncovers a previously unrecognized immunometabolism by which SPHK1 controls B cell function, highlighting its therapeutic potential for enhancing anti-tumor immunity and improving immunotherapy responsiveness. Citation Format: Mona Singh, Prachi Gupta, Arezou Rahimi, Sunila Pradeep. The Sphk1-B cell axis as a targetable immunoregulatory pathway in cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7941.
Singh et al. (2026) studied this question.