Nano-Immunotherapy Targeting TAMs: Precisely Regulating TAMs to Reverse Immunosuppressive TME

Abstract: Given the crucial role of tumor-associated macrophages (TAMs) in cancer development, nano-immunotherapy targeting TAMs represents a pivotal strategy for reversing the immunosuppressive tumor microenvironment (TME) and inhibiting cancer progression. Nano-drug delivery systems have evolved into multimodal platforms that utilize multi-drug synergy and integrated physical energy interventions, showing considerable potential for enhancing drug targeting and biocompatibility. The core objective of TAM-targeted nano-immunotherapy lies in the precise regulation and functional remodeling of TAMs, as well as the synergistic reversal of the immunosuppressive TME. This review addresses the knowledge gaps and challenges in nano-immunotherapy targeting TAMs and explores recent advances in TAM-targeted immunotherapy using various strategies and nanocarriers, with particular emphasis on the relevant cell surface receptors and downstream signaling pathways. Nano-immunotherapeutic strategies targeting TAMs include reprogramming TAMs, influencing TAM polarization, regulating TAM-secreted mediators, inducing TAM exhaustion, enhancing TAM phagocytosis, modulating TAM metabolism, inhibiting TAM recruitment, and blocking PD-L1 expression on TAMs. The innovations of nanocarriers involve the entire chain intelligent design from inorganic nanocrystals, organic polymers to organic-inorganic hybrid systems, and the precise “Trojan horses” constructed using biodegradable polymers and biomimetic membrane vesicles. Intelligent nanorobots targeting TAMs, as autonomous diagnostic and therapeutic systems integrating sensing, decision-making, and execution, represent an effective approach to enhancing the precision and intelligence of anti-tumor strategies. The image shows a central cell (TAM) surrounded by various nano-drug delivery systems. In the top left, a diagram illustrates stemness with arrows pointing from a central cell to various differentiated cells. Below, a section labeled ’Metastasis’ shows tumor-associated macrophages and cytokines interacting with tumor cells, indicating movement across a membrane. The central image depicts a large cell with various nano-drug delivery systems inside. In the top right, a diagram labeled ’Drug resistance’ shows self-renewal and downregulation of MHC-I involving CD8 T cells and TCR. The bottom right section labeled ’Immunosuppressive TME’ illustrates a tumor microenvironment with various immune cells and structures. Each section highlights different aspects of tumor progression influenced by nano-immunotherapy targeting TAMs.TAM surrounded by various nano-drug delivery systems: stemness, metastasis, drug resistance and immunosuppressive TME. Keywords: tumor-associated macrophages, immunotherapy, targeting, nanocarrier, cancer