Divergent oncogenic signaling and immune microenvironment changes in low-grade serous ovarian cancer patients undergoing intraperitoneal chemotherapy.

Low-grade serous ovarian carcinoma (LGSOC) is a rare, treatment-resistant subtype of ovarian cancer characterized by peritoneal spread. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) delivers chemotherapy directly into the abdomen during serial laparoscopic surgeries, enabling repeated sampling of tumors for longitudinal analysis. Using single-nuclei RNA sequencing on 15 tumor samples across PIPAC cycles in two patients (a responder and a non-responder), we tracked molecular and cellular changes over time. Non-responder tumors showed upregulation of proliferation pathways (E2F, MYC, G2/M), KRAS signaling, epithelial-mesenchymal transition, and unfolded protein response, correlating with resistance. Responder tumors exhibited downregulation of proliferation and stress pathways but activated alternative survival mechanisms (PI3K, Wnt/β-catenin, Notch). Archetype analysis revealed dynamic shifts in metabolic and immune-related subpopulations in the responder tumors, while immunoprofiling showed greater immunosuppression in non-responder tumors. Despite the small cohort, these exploratory observations highlight tumor adaptation and underscore the need for multi-targeted therapies addressing proliferation, stress, survival, and immune evasion.