Stromal Stiffness-Regulated IGF2BP2 in Pancreatic Cancer Drives Immune Evasion via Sphingomyelin Metabolism.

Background & Aims: Immunotherapy has shown promising results in cancer treatment; however, it remains largely ineffective for pancreatic ductal adenocarcinoma (PDAC). N6-methyladenosine (m6A), known for its crucial role in cancer biology, is not yet fully understood regarding immune evasion. This study aims to elucidate the associations and mechanisms linking m6A modification with immune evasion in PDAC and propose strategies for clinical intervention.

Methods: A multimodal PDAC cohort of 122 patients was developed, integrating transcriptomic profiling, imaging mass cytometry, and m6A quantification to identify m6A regulators associated with immunosuppressive tumor microenvironment (TME) and clinical outcomes. Findings were validated across 6 independent PDAC cohorts. Assays including MeRIP, RIP, and RNA pull-down confirmed that IGF2BP2 binds to targets, whereas single-cell RNA-sequencing, flow cytometry, and multiplex immunohistochemistry profiled the TME. Preclinical interventions were tested in PDAC organoids, patient-derived tissue fragments, and humanized mouse models.

Results: Our comprehensive analysis identified the m6A reader protein IGF2BP2 as a critical factor associated with poor prognosis in PDAC, linked to reduced effector cell infiltration and a fibrotic TME. High matrix stiffness in PDAC stabilized IGF2BP2, which subsequently promoted sphingomyelin synthesis via SGMS2 up-regulation. This pathway facilitates PD-L1 localization on membrane lipid rafts, enhancing immune evasion. The elastographic properties of PDAC enabled noninvasive screening of patients with overexpressed IGF2BP2/SGMS2. Disrupting sphingomyelin synthesis improved antitumor immunity and suppressed PDAC growth in humanized mice, highlighting immunotherapeutic opportunities for PDAC.

Conclusions: These findings emphasize the critical interplay between extrinsic matrix stiffness and intrinsic IGF2BP2-regulated sphingomyelin synthesis, identifying a promising target for immunotherapeutic strategies in PDAC.