After decades of development and accumulation, chimeric antigen receptor (CAR)-T therapy has become a revolutionary immunotherapy method, which has triggered changes in treatment methods and concepts in the fields of cancer, autoimmune disorders, infection, fibrosis and other diseases. With the continuous expansion of indications and potential application fields, adoptive CAR-T therapy products are difficult to meet the expanding market demand and provide equal access to treatment due to their technical complexity and substantial production costs. These factors drive the development and practice of novel technologies, in this context, in vivo CAR-T therapy has been proposed: the in vivo or in situ programming of CAR-T cells to eliminate pathological cells through the delivery of CAR genes in vivo by viruses or engineered nanoparticles. This new technology pathway simplifies the manufacturing and therapeutic procedures, reduces treatment costs, and improves patient accessibility, which has excellent potential for clinical application. This article reviews recent advances in in vivo CAR-T therapy, compares the advantages and characteristics of this approach with traditional adoptive therapy, discusses the therapeutic risks and related challenges of in vivo CAR-T therapy, and emphasizes the guiding significance of adoptive therapy-based enhancement strategies for the development of in vivo CAR-T therapy.

Immune cell therapy based on chimeric antigen receptor (CAR) technology platform has been greatly developed. The types of CAR immune cell therapy have expanded from T cells to innate immune cells such as NK cells and macrophages, and the diseases treated have expanded from hematological malignancies to non-tumor fields such as infectious diseases and autoimmune diseases. Among them, CAR-T and CAR-NK therapy have observed examples of rapid remission in approved clinical trials, but the efficacy is unstable and plagued by tumor resistance. Trogocytosis is a special phenomenon of intercellular molecular transfer that is common in the immune system and is achieved by recipient cells through acquisition and internalization of donor cell-derived molecules and mediates immune effects. Recently, a novel short-term drug resistance mechanism based on trogocytosis has been proposed, and the bidirectional molecular exchange between CAR immune cells and tumor cells triggered by trogocytosis partially explains the long-term relapse phenomenon after treatment with CAR immune cells. In this review, we summarize the research progress of trogocytosis in CAR immunotherapy, discuss the influencing factors of trogocytosis and its direct and indirect interference with CAR immune cells and emphasize that the interference of trogocytosis can further release the potential of CAR immune cell therapy.

Chimeric antigen receptor macrophage (CAR-M) therapy has emerged as a highly promising novel platform in solid tumor immunotherapy. Leveraging its inherent tumor-homing capacity, potent phagocytic function, and potential to remodel the tumor microenvironment (TME), CAR-M offers a new strategic approach to address the limitations faced by CAR-T therapy in solid tumors, such as poor infiltration and immunosuppression. Despite these mechanistic advantages, clinical outcomes with first-generation CAR-M constructs have been modest, largely due to their limited in vivo persistence and effector activity. In this review, we summarize the core challenges limiting the efficacy and clinical application of CAR-M, and provide an in-depth discussion of engineering strategies aimed at enhancing its anti-tumor activity through optimization of the CAR molecular structure. Beyond CAR-M engineering, we also outline recent advances in combining CAR-M with other therapeutic modalities and discussing their underlying synergistic mechanisms. Looking forward, we highlight next-generation CAR-M platforms, such as in vivo edited CAR-M and CAR-monocytes, which aim to simplify manufacturing, reduce costs, and enable more precise immune modulation. Although challenges remain in manufacturing, durability of response, and safety, continuous technological innovation and rational combination strategies are accelerating the translation of CAR-M therapy from proof-of-concept toward clinical application, holding promise for opening new avenues in solid tumor treatment.

Macrophages have garnered notable interest as therapeutic vehicles due to their innate phagocytic ability, tumor tropism, and pivotal role in linking innate and adaptive immunity. These attributes have led to the development of various macrophage‑centered treatments. Among them, chimeric antigen receptor macrophages (CAR‑Ms) have emerged as a promising adoptive cell therapy, demonstrating potential for clinical application in multiple solid tumors. However, their effector functions remain amenable to further enhancement. In the present study, anti‑HER2 CAR‑Ms were constructed using an adenoviral vector system. The specificity and antitumor efficacy against HER2⁺ ovarian cancer cells were assessed using flow cytometry. The effects of a CD47 monoclonal antibody (mAb) on CAR‑M‑mediated killing and phenotypic polarization were subsequently investigated. Additionally, the combined therapeutic benefit of CD47 mAb and anti‑HER2 CAR‑Ms was evaluated in a murine subcutaneous xenograft model of ovarian cancer. Anti‑HER2 CAR‑Ms specifically recognized and killed HER2‑expressing ovarian cancer cells. The addition of CD47 mAb enhanced the phagocytic capacity, promoted a pro‑inflammatory phenotype and inflammatory cytokine secretion in CAR‑Ms. In vivo, combination therapy significantly reduced tumor burden in xenograft‑bearing mice. Collectively, these findings indicate that the combination of CAR‑Ms with CD47 blockade offers a robust and promising strategy for personalized targeted therapy in solid tumors.