In a recent paper published in 2025 Nature Communications, Pierini et al. [1] demonstrated that chimeric antigen receptor macrophages (CAR-M) enhance the efficacy of programmed cell death protein 1 (PD-1) immune checkpoint blockade in HER2⁺ solid tumors. Using a syngeneic HER2+ mouse model, the study revealed that CAR-M therapy successfully reprograms the immunosuppressive tumor microenvironment (TME), promotes infiltration of CD8+ cytotoxic T cells (CTLs), natural killer (NK) cells, and promotes durable antigen spreading. Notably, CAR-M therapy provided protection against antigen-negative tumor relapses, a significant clinical challenge associated with current CAR-T therapies. These findings support the potential of CAR-M as a transformative adjunct to current immunotherapy strategies. Immune checkpoint inhibitors (ICIs) targeting PD-1 or programmed death ligand 1 (PD-L1) have revolutionized cancer immunotherapy, especially in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma. However, their limited efficacy in solid tumors is due to multiple resistance mechanisms, including a suppressive TME dominated by tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), poor antigen presentation, and inadequate T-cell infiltration. While CAR-T therapies have demonstrated remarkable success in hematological malignancies, their limited effectiveness in solid tumors remains suboptimal. These limitations underscore the urgent need for new approaches capable of overcoming immunosuppression and enhancing antigen presentation within the TME [2]. To overcome these challenges, CAR-M therapy represents a novel and promising immunotherapeutic modality. Macrophages are naturally equipped to infiltrate tumors, phagocytose cancer cells, and cross-present tumor antigens to the adaptive immune system [3]. By engineering macrophages to express a CAR targeting a tumor-associated antigen (e.g., HER2), researchers aim to redirect these cells toward tumor destruction while harnessing their innate antigen-presenting capacity. Unlike CAR-T cells, CAR-Ms are not MHC-restricted and can engage tumors through both direct cytotoxicity and activation of other immune components. This dual functionality gives CAR-M therapy a unique advantage, convert immunologically “cold” tumors into “hot,” immune-active sites. In the HER2+ mouse model, Pierini et al., administered intratumoral injections of anti-HER2 CAR-M and observed a marked increase in the infiltration of CD8⁺ T cells, CD4⁺ helper T cells, NK cells, and dendritic cells (DCs) [1]. CAR-M treatment also reprogrammed endogenous macrophages from a M2-like, pro-tumor phenotype to an M1-like, pro-inflammatory state. Importantly, this intervention led to robust antigen spreading, a phenomenon in which T cells begin to recognize and respond to tumor antigens beyond the initial CAR target [3]. Antigen spreading is a crucial mechanism for achieving a long-term immune response and limiting relapse from tumor antigen escape variants. A key finding of the study was the demonstrated synergy between CAR-M therapy and PD-1 blockade. While PD-1 inhibitor monotherapy showed limited efficacy against HER2+ tumors, the combination of CAR-M therapy with PD-1 antibodies resulted in significantly improved tumor control and prolonged survival [1]. Mechanistically, this synergistic effect is attributed to CAR-M-induced remodeling of the TME, reducing suppressive populations, increasing DC priming of T cells, and improving infiltration and expansion of effector lymphocytes [1, 4]. These results support a new therapeutic paradigm, positioning CAR-M not only as a standalone therapy but also as a valuable adjuvant that amplifies the therapeutic window of ICIs [4]. The translational potential of this approach is already being evaluated. A first-in-human phase I clinical trial (NCT04660929) is currently evaluating the safety and feasibility of CT-0508, an autologous anti-HER2 CAR-M product, in patients with HER2-overexpressing advanced solid tumors [5]. While the current trial focuses on CAR-M monotherapy, future clinical investigations aim to investigate its combination regimens with ICIs, such as pembrolizumab. Early findings suggest encouraging immune cell infiltration and reductions in circulating tumor DNA (ctDNA) in some patients, supporting the potential of CAR-M therapy to expand the reach of immunotherapy in advanced breast, gastric, or ovarian cancers overexpressing HER2. Despite these promising preclinical and early clinical data, several challenges remain before CAR-M achieve widespread clinical utility. The manufacturing process for CAR-M involves complex genetic modification and ex vivo differentiation of monocytes into macrophages, requiring meticulous quality control and scalability [3]. Additionally, preclinical studies indicate that CAR-M cells may exhibit limited in vivo persistence, potentially curtailing their long-term efficacy [3]. Approaches to improve CAR-M durability include mRNA stabilization, repeated dosing, and incorporation of costimulatory domains in the CAR construct. Monitoring for toxicities, including cytokine release syndrome (CRS), is also essential, though early data suggest that CAR-M therapy is generally well tolerated. Another critical area of development is the optimization of antigen targets. While HER2 is an ideal proof-of-concept target due to its overexpression in multiple tumor types, identifying additional tumor-associated antigens with high specificity remains a priority. Moreover, biomarker-guided patient selection will be vital to determine which patients are most likely to benefit from CAR-M therapy, particularly when considering combination approaches with ICIs, chemotherapy, or radiation. While CAR-M research has largely focused on solid tumors, emerging evidence suggests potential applications in hematologic malignancies. In contrast to CAR-T cells that rely on TCR engagement, CAR-Ms function independently of MHC and may offer advantages in treating MHC-low or immune-escaped myeloid leukemias [3]. Engineered macrophages may also facilitate phagocytosis of malignant hematopoietic cells and enhance immune surveillance in the bone marrow microenvironment. Although still largely theoretical, these exploratory directions warrant further preclinical investigation. A graphical summary of CAR-M therapy and PD-1 blockade synergy in HER2+ solid tumors is shown in Figure 1. CAR-M therapy remodels the immunosuppressive TME, augments immune cell recruitment, enhances antigen presentation, and restores T-cell cytotoxicity when combined with PD-1 blockade, offering a promising avenue for overcoming resistance in solid tumors. Integrating CAR-M into existing immunotherapy frameworks represents a highly promising therapeutic frontier. Future research directions should focus on identifying additional tumor-specific targets amenable to CAR-M therapy, optimizing CAR construct designs to enhance macrophage functionality, and exploring innovative combinational strategies beyond PD-1 blockade, such as chemotherapy or radiation therapy. Additionally, refining biomarker-guided patient selection will be crucial to maximizing therapeutic outcomes. Results from ongoing and planned clinical trials will be instrumental in validating the therapeutic potential of CAR-M and, if successful, could significantly reshape the landscape of cancer immunotherapy, particularly for patients with treatment-resistant solid malignancies. In conclusion, CAR-M therapy represents a groundbreaking addition to the immunotherapy arsenal. Its ability to reshape the tumor immune landscape, promote antigen spreading, and synergize with checkpoint blockade holds promise for treating solid tumors previously refractory to immune-based therapies. As clinical trials progress, future studies should aim to refine CAR-M engineering for enhanced persistence, expand the repertoire of actionable tumor targets, and develop personalized treatment strategies informed by immune profiling and biomarker discovery [3]. If successful, CAR-M could help realize the full potential of macrophage-based immunotherapy and redefine the boundaries of immune intervention in cancer care. Wenxue Ma: conceptualization, investigation, writing – original draft, validation, visualization, writing – review and editing, software, formal analysis, project administration, data curation, supervision, resources. Catriona Jamieson: conceptualization, funding acquisition, writing – review and editing, project administration, supervision, resources, validation. Both authors have read and approved the final manuscript. The figure was created with BioRender. This study was supported by grants of NASA Research Announcement (NRA) NNJ13ZBG001N and NIH/NCATS UL1TR001442N. The authors have nothing to report. The authors declare no conflicts of interest. Data availability is not applicable to this highlight as no new data were created or analyzed in it.