High grade serous ovarian cancer (HGSOC) is the most aggressive subtype of ovarian cancer. HGSOC is characterized by high inter- and intra-tumoral heterogeneity, which contributes to chemotherapy resistance. Patient-derived organoids (PDOs) are valuable preclinical models to elucidate the biology of human cancers and to test their response to treatments. This study aims at characterizing the cellular heterogeneity of PDOs and to uncover vulnerabilities of chemotherapy resistant HGSOC.

Single-cell transcriptomics of PDOs developed from biopsies of platinum-resistant and platinum-sensitive HGSOC. Chemotherapeutic treatments of HGSOC PDOs and of ascitic-derived ovarian cancer cells and immunohistochemistry analyses of tissues from independent HGSOC patients.

HGSOC PDOs comprise subclusters of cells exhibiting different transcriptional states and patient-specific signatures. Proliferative and non-proliferative subclusters co-exist in PDOs and their relative proportion is altered by chemotherapy. Proliferative cell sub-populations exhibit expression of cell cycle and DNA damage response related genes, whereas non-proliferative sub-populations display inflammatory signatures. Furthermore, sensitivity to platinum-based treatments was inversely correlated with oxidative phosphorylation (OXHPOS) in PDOs, indicating a metabolic switch associated with chemoresistance. Accordingly, platinum-resistant PDOs and ascitic HGSOC cells show higher sensitivity to OXHPOS inhibition. We found that neoadjuvant chemotherapy (NACT) directly up-regulates oncogenic and metabolic pathways that are involved in development of recurrence, such as the MYC and OXPHOS genes. NACT also induces the expression of major histocompatibility complex type II (MHC-II) molecules. Immunohistochemistry confirmed MHC-II up-regulation in post-NACT biopsies, indicating that tumour cells mount a general antigen-presenting response upon chemotherapy, associated with recruitment of infiltrating immune cells.

PDOs maintain the inter- and intra-tumoral cellular heterogeneity of HGSOC. Chemotherapy targets proliferative cell subclusters, sparing non-proliferative ones. Dependency on OXPHOS represents an actionable vulnerability in PDOs, which can be exploited to hijack chemoresistance. Sequential chemotherapy and immunotherapy may also improve clinical response of HGSOC patients.

High grade serous ovarian cancer

Patient-derived organoids

Platinum resistance

Oxidative phosphorylation

Major histocompatibility complex type II

© 2026 The Author(s). Published by Elsevier Ltd.