Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer.

Immunotherapy has shown limited success in recurrent ovarian cancer (OC), with prognostic insights largely derived from treatment-naive tumors. We analyzed 697 tumor samples (566 primary and 131 recurrent) from 595 OC patients across five independent cohorts, capturing tumor-infiltrating lymphocytes (TILs) heterogeneity and identifying four immune phenotypes linked to prognosis and TIL:myeloid networks driving malignant progression. We found that in preclinical mouse models, mirroring inflamed human OCs, the recurrent Brca1(mut) tumors maintained activated TILs:dendritic cells (DCs) niches but evaded immune control through upregulation of COX/PGE(2) signaling. Conversely, recurrent Brca1(wt) tumors displayed loss of TILs:DCs niches and accumulated immunosuppressive tumor microenvironment (TME) networks featuring Trem2/ApoE(high) tumor associated macrophages (TAMs) and Nduf4l2(high)/Galectin3(high) malignant states. Recurrent tumors recapitulate the immunogenic landscapes of original cancers. Our findings reveal BRCA-dependent TIL:myeloid crosstalk as key to persistent immunogenicity in recurrent OC and propose new targets to enhance chemotherapy efficacy.