<scp>CD81</scp> Aggravates Ovarian Cancer Progression via p‐Cresyl Sulfate‐Mediated Mitophagy in Tim4⁺ Tumour‐Associated Macrophages

Ovarian cancer (OC) is characterised by widespread peritoneal metastasis. Tetraspanin CD81 is predominantly located at the cellular membrane and exhibits inconsistent roles in tumour progression. However, its precise function in OC remains unclear. We found that CD81 expression was significantly elevated in tumour tissues from OC patients with poor prognosis, and it directly promoted proliferation, and migration of OC cells. Stable knock-down of CD81 expression ameliorated disease progression in a murine model of OC and induced metabolic responses in OC cells. Metabolomics and mass spectrometry identified the protein-bound toxin p-cresyl sulfate (PCS) as a key metabolite regulated by the CD81-FAK signalling axis. One aspect is that PCS promoted the growth of OC cells. Furthermore, tumour-derived PCS combined with Cdh1 to enhance Bnip3-dependent mitophagy activity of Tim4 positive tumour-associated macrophages (TAMs). Intraperitoneal injection of PCS reversed the therapeutic effects observed following CD81 knock-down; the mitophagy of reprogrammed Tim4⁺ TAMs was also promoted, accompanied by alterations in antitumor immunity. In summary, we elucidated CD81 prompted Tim4⁺ TAMs mitophagy to induce OC progression via FAK/PCS/Cdh1 pathway, deepen our understanding of OC pathogenesis.