Targeting stromal cells to overcome immunotherapy resistance in solid tumors

Despite breakthrough advances in cancer immunotherapy, primary and acquired resistance in solid tumors remain significant clinical challenges. Accumulating evidence indicates that multiple stromal components including fibroblasts, adipocytes, vascular cells, and platelets, actively contribute to tumor progression through diverse mechanisms. These components establish physical barriers and foster immunosuppressive niches, collectively forming a protective shield that facilitates tumor immune evasion. Although numerous challenges await resolution, targeting stromal cells has emerged as a promising strategy to overcome resistance to immunotherapy in solid tumors. Moreover, the unique biological properties of stromal cells are being exploited to develop innovative antitumor approaches, thereby expanding the current therapeutic arsenal against cancer. In this review, we systematically delineate how stromal cells regulate tumor proliferation, metastasis, and immune evasion, with particular emphasis on their dynamic crosstalk with immune cells. Additionally, we summarize the opportunities and challenges associated with combining stromal-targeting therapies with immunotherapy, providing a theoretical framework and novel therapeutic paradigms to optimize treatment strategies and advancing integrated antitumor approaches.