CAR-macrophages: a new chapter in cancer immunotherapy

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy achieves remarkable success in hematological cancers, but its efficacy is severely limited in solid tumors by formidable obstacles including physical barriers, the highly immunosuppressive tumor microenvironment (TME), and antigen escape. To address these persistent challenges, chimeric antigen receptor-macrophage (CAR-M) therapy emerges as a promising alternative, leveraging intrinsic advantages of macrophages like unparalleled tumor infiltration, powerful phagocytosis, and high plasticity. The evolution of CAR-M is primarily defined by the intracellular signaling domain. CAR-M exerts its anti-tumor effects through multifaceted mechanisms, including direct enhanced phagocytosis and tumor cell killing, TME remodeling by repolarizing to a pro-inflammatory M1-like phenotype, releasing anti-tumor effectors, and degrading the extracellular matrix (ECM), and the activation of adaptive immunity via efficient antigen presentation. Despite its promise, CAR-M faces hurdles such as TME physical barriers and the potential for M2-like re-education. Current optimization strategies focus on enhancing tumor infiltration, overcoming immunosuppression with “armored” CAR-Ms, and improving safety with suicide switches. Encouraging pre-clinical data accelerates CAR-M into early-phase clinical trials for solid tumors, and the platform’s utility is also being explored beyond oncology in infectious, autoimmune, and neurodegenerative diseases.

1. Introduction

Despite significant advancements in diagnosis and treatment, cancer remains a formidable challenge and a global health crisis. Conventional approaches like surgery, radiation, and chemotherapy are often hampered by widespread side effects, drug resistance, and limited effectiveness against advanced or metastatic tumors [1]. This persistent unmet need has spurred a revolution in oncology, the emergence of immunotherapy. The most significant breakthrough in this new era is adoptive cell therapy, exemplified by chimeric antigen receptor T (CAR-T) cell therapy. CAR-T therapy has demonstrated extraordinary success in treating blood cancers, especially B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma, achieving high response rates and long-lasting remissions in patients who have not responded to other treatments [2,3]. These achievements have ignited immense enthusiasm for harnessing the power of the immune system to combat cancer.

However, the impressive efficacy of CAR-T cell therapy in liquid tumors has not been consistently replicated in solid tumors, which constitute over 90% of all cancer diagnoses. CAR-T cells face a multitude of complex challenges within the solid tumor microenvironment (TME) [4,5]. Firstly, the dense extracellular matrix (ECM) and irregular blood vessels in solid tumors form physical barriers that hinder CAR-T cells from reaching and infiltrating the tumor’s core [4–6]. Secondly, solid tumors create a highly immunosuppressive TME, filled with inhibitory cytokines like TGF-β and IL-10, immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2-polarized tumor-associated macrophages (TAMs), along with metabolic stresses like hypoxia, acidosis, and nutrient scarcity [4,5]. These factors often render CAR-T cells inactive, leading to functional impairment [7]. Additionally, tumor cells frequently exhibit antigen heterogeneity, with varying antigen expression levels that can result in antigen escape and tumor recurrence [4,5,8]. The shared expression of antigens between tumors and healthy tissues can also cause severe on-target, off-tumor toxicities [4,5]. Moreover, the harsh TME can lead to rapid exhaustion and apoptosis of CAR-T cells, compromising long-term efficacy. These inherent limitations underscore the urgent need for alternative cellular immunotherapy approaches to effectively combat solid tumors [4,5,8].