<p>The aggressive progression and significant chemotherapy resistance of ovarian clear cell carcinoma (OCCC) are closely related to the immunosuppressive tumour microenvironment (TME), but its potential molecular drivers are still unclear. The core of this process is the M2 polarisation of tumour-associated macrophages (TAMs), which regulates the tumour-promoting microenvironment. This study reveals a new and key signal axis responsible for this pathological intercellular dialogue. We confirmed that TREM2 is highly expressed on OCCC-related TAMs and plays a key role in its M2 differentiation. In terms of mechanism, we found that TREM2 bypassed its classic signal adaptor and directly interacted with the calcium-binding protein S100A9. This unprecedented interaction acts as a molecular switch, specifically activating the IL-17 signalling pathway. As a result, the TREM2-S100A9-IL-17 cascade reaction strongly drives M2 polarisation, which in turn promotes the proliferation, migration and invasion of OCCC cells. The key is to inhibit IL-17A by gene silencing S100A9 or using the pharmacology of clinical-grade antibody secukinumab. These tumour-promoting effects are completely eliminated in both in vitro and preclinical xenotransplantation models. This study reveals a new mechanism by which macrophages drive cancer progression, and determines that the TREM2-S100A9-IL-17 axis is a key molecular weakness, which provides a strong basis for the reuse of anti-IL-17 therapy to disintegrate the OCCC immunosuppression barrier.</p>