The next frontier in immunotherapy: potential and challenges of CAR-macrophages

Chimeric antigen receptor macrophage (CAR-M Phi) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-M Phi offers a promising approach to target and eradicate tumor cells by utilizing macrophages' phagocytic and antigen-presenting abilities. However, challenges such as the complex tumor microenvironment (TME), variability in antigen expression, and immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of CAR-M Phi action, optimal construct designs, and interactions within the TME. It also delves into the ex vivo manufacturing challenges of CAR-M Phi, discussing autologous and allogeneic sources and the importance of stringent quality control. The potential synergies of integrating CAR-M Phi with existing cancer therapies like checkpoint inhibitors and conventional chemotherapeutics are examined to highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways for CAR-M Phi therapies are scrutinized alongside established protocols for CAR-T cells, identifying unique considerations essential for clinical trials and market approval. Proposed safety monitoring frameworks aim to manage potential adverse events, such as cytokine release syndrome, crucial for patient safety. Consolidating current research and clinical insights, this review seeks to refine CAR-M Phi therapeutic applications, overcome barriers, and suggest future research directions to transition CAR-M Phi therapies from experimental platforms to standard cancer care options. CAR-M Phi offers an innovative approach to treating solid tumors, addressing the limitations of traditional CAR-T therapies.CAR-M Phi eliminates tumor cells and boosts other immune cells' effectiveness.Strategies are being t developed to improve CAR-M Phi targeting and cancer cell eradication.CAR-M Phi is combined with other treatments to enhance overall efficacy.Challenges and safety concerns, including side effects of CAR-M Phi therapies, are Beijing addressed.