The pivotal role of macrophages in tumorigenesis and pioneering cancer immunotherapy across pre-clinical and clinical frontiers

Tumor-associated macrophages (TAMs) are among the most abundant cells in the tumor microenvironment (TME), with M1 and M2 polarization exhibiting anti-tumorigenic and tumorigenic functions, respectively. Originating from both embryonic precursors and circulating monocytes derived from hematopoietic stem cells, TAMs acquire distinct transcriptional, metabolic, and functional identities shaped by the TME. The interactions in the TME among various cells, including cancerous and non-cancerous cells, can determine the polarization and function of TAMs within the tumor. More recently, TAMs have garnered significant interest as a promising therapeutic target in oncology. The TAMs have been shown to enhance proliferation, metastasis, and angiogenesis in human cancers. Notably, cytokines and chemokines, among others, can regulate the infiltration of TAMs in TME. Given the crucial role of macrophages in regulating inflammation and immune responses, targeting these cells has become a significant focus in cancer immunotherapy. Currently, macrophages have been targeted through three strategies, including suppressing macrophage/monocyte recruitment, depletion of TAMs, and re-education of TAMs. Each of these approaches is being investigated in preclinical models and clinical trials, either as monotherapy or in combination with immune checkpoint inhibitors. TAMs can also be engineered to act as drug delivery tools, carrying nanoparticles directly into tumors. In the clinic, some types of TAMs, marked by proteins like CD163 and CD204, can help predict patient outcomes in several cancers. This review investigates the origins of TAMs and the mechanisms underlying their polarization and metabolism. Furthermore, we study macrophage-driven tumor progression and devising effective targeting strategies, as well as challenges that remain and where the field may go next in macrophage-based cancer treatment. Going forward, combining single-cell profiling with multi-target therapies may offer the best path toward more effective, TAM-based cancer treatments.