Reprogramming tumor-associated macrophages as a unique approach to target tumor immunotherapy

Abstract

In the last ten years, it has become increasingly clear that tumor-infiltrating myeloid cells drive not just carcinogenesis via cancer-related inflammatory processes, but also tumor development, invasion, and metastasis. Tumor-associated macrophages (TAMs) in particular are the most common kind of leucocyte in many malignancies and play a crucial role in establishing a favorable microenvironment for tumor cells. Tumor-associated macrophage (TAM) is vital as the primary immune cell subset in the tumor microenvironment (TME).In order to proliferate and spread to new locations, tumors need to be able to hide from the immune system by creating an immune-suppressive environment. Because of the existence of pro-tumoral TAMs, conventional therapies like chemotherapy and radiotherapy often fail to restrain cancer growth. These cells are also to blame for the failure of innovative immunotherapies premised on immune-checkpoint suppression. Understanding the series of metabolic changes and functional plasticity experienced by TAMs in the complex TME will help to use TAMs as a target for tumor immunotherapy and develop more effective tumor treatment strategies. This review summarizes the latest research on the TAMs functional status, metabolic changes and focuses on the targeted therapy in solid tumors.

Delineation of signaling routes that underlie differences in macrophage phenotypic states

“…Because of their fundamental role in cancer and other diseases, there is a strong interest in finding clinically relevant macrophage populations [127][128][129] and identifying markers and regulators of the specific cell states 24,130 . Clinical trials that aim to modulate immunosuppressive macrophages include targeting of the CSF1R receptor, delivery of IRF5 and IRF8 TFs that upregulate pro-inflammatory genes, or activation of toll-like receptors [131][132][133] . On the example of pro-inflammatory macrophages, we show here that unbiased proteomic signatures can be a powerful means for the categorization of macrophages found in the TIME.…”

High infiltration of CD209+ dendritic cells and CD163+ macrophages in the peritumor area of prostate cancer is predictive of late adverse outcomes

“…showed in an experimental model of melanoma resistant to PD-1 blockade that depletion of CD163 + macrophages resulted in a massive infiltration of activated T cells and ultimately, in tumor regression ( 56 ). MΦ-targeting immunotherapy approaches consisting in reprogramming of tumor-associated MΦ are being developed and hopefully will lead to more effective tumor treatment strategies ( 57 ).…”

Unraveling the enigma of tumor-associated macrophages: challenges, innovations, and the path to therapeutic breakthroughs

“…Recent evidence suggests that M2-type macrophages, similar to TAMs, serve as prognostic markers for gastric cancer ( 119 ). Instead of eliminating TAMs altogether, current therapeutic strategies aim to modify their behavior by converting pro-tumorigenic M2-like TAMs into anti-tumor M1-like forms ( 14 ). This approach retains TAMs’ essential roles in tissue repair and homeostasis while harnessing their potential in the fight against cancer.…”

“…The utilization of TAMs as prognostic tools in clinical settings is on the rise, particularly in the context of therapeutic reprogramming. Instead of complete TAM removal, current strategies focus on behavior modification, transitioning pro-tumorigenic M2-like TAMs into anti-tumor M1-like counterparts ( 7 , 14 ). This strategy maintains the advantageous properties of TAMs in tissue repair and homeostasis while engaging them in the battle against cancer.…”

“…Furthermore, we investigate the potential of merging TAM-targeted strategies with conventional treatments, covering chemotherapy, radiation, and immunotherapy. This includes the innovative concept of utilizing reprogrammed TAMs for cancer immunotherapy ( 14 ) and employing single-cell-based technologies for personalized therapeutic interventions ( 15 ).…”