Divergent Oncogenic Signaling and Immune Microenvironment Changes in Low-Grade Serous Ovarian Cancer Undergoing Intraperitoneal Treatment

Low-grade serous ovarian carcinoma (LGSOC) is a rare, therapeutically challenging subtype of epithelial ovarian cancer characterized by high recurrence rates and intrinsic resistance to conventional therapies. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) represents an innovative approach primarily facilitating repeated intraperitoneal sampling, enhancing the opportunity to study molecular responses to chemotherapy in detail, though its direct impact on LGSOC remains understudied. Here, we uniquely conducted longitudinal single-nuclei RNA sequencing on tumor samples from two extensively pretreated LGSOC patients undergoing sequential chemotherapy cycles via PIPAC, enabling the tracking of dynamic molecular and cellular shifts. Our analysis revealed profound differences between responder and non-responder profiles. The non-responder demonstrated significant upregulation in proliferation-associated pathways (E2F, MYC targets, G2/M checkpoint), KRAS signaling, epithelial-mesenchymal transition, and unfolded protein response (UPR), correlating with aggressive tumor growth and treatment resistance. Conversely, the responder showed downregulation of proliferation-associated pathways, reduced translational activity, and decreased UPR stress signaling, accompanied by compensatory activation of alternative survival pathways including PI3K, Wnt/β-catenin, and Notch signaling. single-nuclei archetype analysis identified dynamic shifts between metabolic and PI3K/immune-enriched subpopulations, highlighting adaptive tumor plasticity under therapeutic pressure. Immunoprofiling revealed marked immunosuppressive microenvironment differences, with substantially elevated regulatory T cells and macrophages in the non-responder, contributing to resistance. These findings emphasize the complexity of therapeutic responses in recurrent LGSOC, underscoring the need for multi-targeted, adaptive treatment strategies that simultaneously address proliferative, stress-related, alternative survival, and immunosuppressive pathways.