Targeting myeloid cells to improve cancer immune therapy

Hui ChenZihan XuJudith Varner^*

• University of California, San Diego, La Jolla, United States

Tumor immunosuppression remains a major barrier to effective cancer immunotherapy and is often driven by the immunoregulatory activities of myeloid cells within the tumor microenvironment (TME). Myeloid populations-including tumor-associated macrophages (TAMs), dendritic cells, granulocytes, and myeloid-derived suppressor cells (MDSCs)-play pivotal roles in dampening anti-tumor immune responses and promoting tumor progression. Recent advances in our understanding of myeloid cell biology have unveiled new therapeutic opportunities to disrupt these immunosuppressive mechanisms. This review highlights key signaling pathways and surface molecules involved in myeloid-mediated immune suppression, including CSF1R, PI3Kγ, mTOR, Syk, MerTK/Axl, and immune checkpoints such as Trem2, LILRBs, VISTA, and CD40. We examine preclinical and clinical findings that support targeting these pathways to reprogram the TME and enhance anti-tumor immunity. By integrating insights from mechanistic studies and therapeutic development, this review underscores the potential of myeloid cell-targeting strategies as promising adjuncts to current cancer immunotherapies. Finally, we discuss future directions and challenges in translating these approaches into durable clinical benefit.