Targeting macrophages in cancer immunotherapy: Frontiers and challenges

J Adv Res. 2025 Oct:76:695-713. doi: 10.1016/j.jare.2024.12.043. Epub 2025 Jan 6.

Abstract

Background: Cancer immunotherapy has emerged as a groundbreaking approach in cancer treatment, primarily realized through the manipulation of immune cells, notably T cell adoption and immune checkpoint blockade. Nevertheless, the manipulation of T cells encounters formidable hurdles. Macrophages, serving as the pivotal link between innate and adaptive immunity, play crucial roles in phagocytosis, cytokine secretion, and antigen presentation. Consequently, macrophage-targeted therapies have garnered significant attention.

Aim of review: We aim to provide the most cutting-edge insights and future perspectives for macrophage-targeted therapies, fostering the development of novel and effective cancer treatments.

Key scientific concepts of review: To date, the forefront strategies for macrophage targeting encompass: altering their plasticity, harnessing CAR-macrophages, and targeting phagocytosis checkpoints. Macrophages are characterized by their remarkable diversity and plasticity, offering a unique therapeutic target. In this context, we critically analyze the innovative strategies aimed at transforming macrophages from their M2 (tumor-promoting) to M1 (tumor-suppressing) phenotype. Furthermore, we delve into the design principles, developmental progress, and advantages of CAR-macrophages. Additionally, we illuminate the challenges encountered in targeting phagocytosis checkpoints on macrophages and propose potential strategies to overcome these obstacles.

Keywords: CAR macrophage; Cancer immunotherapy; Macrophage polarization; Phagocytosis checkpoints.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immune Checkpoint Proteins / metabolism
  • Immunotherapy* / methods
  • Immunotherapy, Adoptive
  • Macrophages* / drug effects
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Neoplasms* / immunology
  • Neoplasms* / pathology
  • Neoplasms* / therapy
  • Phagocytosis / drug effects
  • Phagocytosis / immunology
  • Receptors, Chimeric Antigen / immunology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Tumor-Associated Macrophages / drug effects
  • Tumor-Associated Macrophages / immunology
  • Tumor-Associated Macrophages / metabolism

Substances

  • Immune Checkpoint Inhibitors
  • Immune Checkpoint Proteins
  • Receptors, Chimeric Antigen