Fig. 2. Barriers to immunotherapy in sarcomas and strategies for modulating their tumor microenvironment.

Sarcomas are primarily recognized by their low tumor mutation burden, which classifies them as tumors displaying limited immune reactivity. The immunosuppressive features characterizing the tumor microenvironment (TME) of sarcomas are correlated with the existence of regulatory T cells, tumor-associated macrophages (TAM), and myeloid-derived suppressor cells (MDSCs) (left). These components present prospective targets for crafting immunotherapy approaches with enhanced efficacy in tackling sarcomas (right). A personalized cancer vacccine addresses low tumor mutation burden by utilizing neoantigens to activate precise cytotoxic T cells targeting sarcoma tumors. TAMs can be regulated by inhibiting M2-like TAMs or by stimulating M1-like macrophages to amplify anti-tumor immune responses. Approaches that combine imatinib with CTLA-4 blockade or employ anti-CD25 antibodies alongside PD-1 blockade can control regulatory T cells (T_regs) and improve treatment outcomes. CCR4 inhibitors have shown potential in reducing T_reg infiltration. Cancer-associated fibroblasts (CAFs) expressing LRRC15 have emerged as promising targets, with the antibody-drug conjugate ABBV-085, which targets LRRC15, displaying notable anti-tumor activity in clinical trials. These strategies seek to overcome the immunologically cold TME in sarcomas, enhancing the efficacy of immunotherapy. MSCs, mesenchymal stem cells; IDO, indoleamine 2,3-dioxygenase; TMB, tumor mutation burden; TCR, T cell receptor.