The Frontline of Cancer Warfare: CAR-T vs. CAR-Macrophage Therapies

Antitumor mechanisms of CAR-macrophage therapy. The antitumor mechanisms of CAR-macrophages can be characterized by four main aspects.(A)CAR-macrophages directly kill tumor cells via antigen-specific phagocytosis mediated by the chimeric antigen receptor. (B)CAR-macrophages exhibit profound interactions with endogenous T cells. On one hand, they present phagocytosed tumor antigens to T cells, and on the other hand, CAR-macrophages may facilitate the activation and persistence of endogenous T cells by costimulation.(C) When employing CD147 as the signaling domain, CAR-macrophages can secrete matrix metalloproteinases (MMPs) that degrade the dense extracellular matrix surrounding solid tumors, thereby facilitating the infiltration of other immune cells.(D)CAR-macrophages exhibit an M1-likephenotype, allowing them to secrete proinflammatory cytokines (e.g., IL-1, IL-6, TNF-α) to educate the tumor microenvironment. (This figure was created at

In the ongoing quest to combat cancer, chimeric antigen receptor (CAR) T therapy has emerged as a promising treatment, revolutionizing the way we enhance a patient’s immune cells within the laboratory to escalate their assault on cancerous tumors. However, this innovative therapy encounters significant resistance when deployed against solid tumors due to the dauntingly hostile environment these tumors manufacture within the organs.

Addressing this challenge, another therapeutic contender enters the arena: CAR macrophage therapy. This novel approach ingeniously modifies immune cells known as macrophages with CARs, displaying a potent potential specifically tailored for solid tumors. In this review, we navigate through the labyrinth of CAR-T and CAR macrophage therapies, probing their structural intricacies, their operational tactics against cancer, and the formidable barriers solid tumors present, all the while drawing invaluable lessons from clinical trial experiences.

What sets CAR macrophage therapy apart, as this review suggests, are its two distinct advantages in combatting solid tumors: it deploys a broader spectrum of tumor-fighting strategies and boasts superior access to the very heart of tumor sites. Notwithstanding, it shares with CAR T therapy certain limitations, particularly the challenge of identifying suitable targets on the elusive tumor cells themselves. This review serves not only to juxtapose the two modalities but also to contemplate how they might learn from each other to enhance their effectiveness against solid tumors.

Moreover, we highlight the critical questions that must be addressed by future research. The imperative to identify novel targets for these therapies is underscored, aiming to amplify their safety and efficacy. Additionally, the urgent need for more extensive clinical trials with a laser focus on solid tumors is emphasized, in order to deepen our comprehension of the advantages and potential risks associated with both CAR-T and CAR macrophage therapies.

The cross-pollination of insights and therapeutic strategies between CAR-T and CAR macrophage therapies offers a tantalizing glimpse into the future of oncological treatment. As this field evolves, it becomes increasingly clear that each therapy has much to teach the other, potentially paving the way for a new era in the management and eradication of solid tumors. Through a synergy of innovative research and clinical prowess, we stand on the cusp of transformative advances in cancer therapy.

CAR structures of CAR-T and CAR-macrophage.CAR-T cells have undergone four generations of development (top panel), with each generation possessing distinct cytoplasmic domains. The first-generation CAR-T cells only express CD3ζ as their cytoplasmic signaling domain. The second-generation CAR-T cells incorporate a costimulatory domain, such as CD28 or 4-1BB, to provide a second signal for T cell activation. The third-generation CAR-T cells have two costimulatory domains. The fourth-generation CAR-T cells, in addition to CD3ζ and costimulatory domains, have a cytokine sequence downstream of CD3ζ, which enables them to produce proinflammatory cytokines (e.g., IL-7, IL-33, IL-12) upon antigen recognition. A P2A peptide is added to cleave the cytokine from the antigen receptor. The CAR design employed in CAR-macrophages comprises an antigen binding domain, a hinge region, a transmembranedomain, and a cytoplasmic signaling domain, and exhibits great diversity in their cytoplasmic signaling domains (bottom panel). The signaling domains of CD3ζ and FcRγ can mediate antigen-specific phagocytosis, while CAR-macrophages that utilize CD147 as asignaling domain can secrete matrix metalloproteinases (MMPs) to break down the dense extracellular matrix surrounding solid tumors. Additionally, in a recent study by Niu et al., CCL19, instead of single chain variable fragment (scFv), was utilized as the antigen-binding domain for CAR-macrophages to target an immunosuppressive cell population highly expressing CCR7, instead of scFv. (This figure was created at

The translation of preceeding text in Chinese:



我们的综述表明,对于实体瘤,CAR巨噬细胞疗法可能有两个关键优势。它似乎提供了更广泛的抗肿瘤方法,并且能更好地到达肿瘤部位。然而,它面临着与CAR T疗法类似的问题,例如缺乏肿瘤细胞上的适合靶点。我们还讨论了这些疗法如何能够互相学习,以便在治疗实体瘤方面更加有效。


Reference: Chen K, Liu M- ling, Wang J- cheng, Fang S. CAR-macrophage versus CAR-T for solid tumors: The race between a rising star and a superstar. Biomol Biomed [Internet]. 2023Oct.24 [cited 2023Nov.2];. Available from:

Editor: Ermina Vukalic

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