Supplementary dataset 4

The ovary is susceptible to harmful environmental factors (hEFs). Tumor progression, TP, is an intracorporal hEF. It’s known that TP could impair adjacent tissues through pro-inflammatory cytokines. However, it is unclear whether and how non-reproductive tumor progression, NRTP, impairs ovarian function, making it challenging to target and prevent this harm prior to diagnosis and cancer treatment. To develop the target therapy to protect ovarian function under tumor progression, we employed MCA205 (mouse fibrosarcoma) cell-allotransplanted B6 mice as a basic model (M group), and meanwhile set up two popular therapeutic models—PD-1 monoclonal antibody injection in allotransplanted B6 mice (PD-1 group) and whole cancer cell vaccine (WCV) injection in allotransplanted B6 mice (WCV group) together to facilitate the discovering process. As expected, tumor progression in M group decreased ovarian function multifacetedly. Interestingly, WCV injection significantly reversed these abnormalities, whereas PD-1 did not. Next, plasma cytokine microarray characterized CXCL10 with both the biggest increment in M group and best rescue in WCV group. Next, we baited the only CXCL10 receptor, IL18R1, within ovaries. Furthermore, we found that CXCL10 impaired ovarian function through three pathways: inducing ovarian fibrosis through CXCL10→IL18R1→p-JNK→COL1A1, promoting primordial follicle overactivation through CXCL10→IL18R1→p-AKT, and increasing ovarian inflammation through CXCL10→IL18R1→p-P65. We have also preliminarily verified the CXCL10/IL18R1 axis in MC38 (mouse colon cancer cells) and B16F10 (mouse Melanoma cells)-allotransplanted B6 mice. Finally, we rescued the decreased ovarian function in the M group by blocking the CXCL10→IL18R1 pathway with CXCL10 antibody or a CXCL10–IL18R1 interface peptide, CIBB. This study provides mechanical evidence and translational strategies how tumor progression impairs ovarian functions and how to target-protect ovaries under tumor progression.