{"doi":"10.1002/mog2.70036","title":"Enhancing PD‐1 Blockade With CAR‐Macrophage Therapy in HER2<sup>+</sup> Solid Tumors","abstract":"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-","journal":"MedComm – Oncology","year":2025,"id":574287,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":477605,"name":"Catriona Jamieson","orcid":"0000-0001-8057-6613","position":1,"is_corresponding":false},{"id":666849,"name":"Wenxue Ma","orcid":"0000-0001-9228-6162","position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":null,"created_at":"2026-07-19T02:57:40.686992Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}