Journal for Immunotherapy of Cancer | Tumor Microenvironment Determines Macrophage Sensitivity to Bexmarilimab

This study systematically analyzed the response mechanisms of bexmarilimab in different tumor microenvironments (TME) using a patient-derived explant culture (PDEC) model, revealing the critical roles of TME and macrophage subtypes in therapeutic responses during immune checkpoint therapy.

 

Literature Overview
This article, "Macrophage sensitivity to bexmarilimab-induced reprogramming is shaped by the tumor microenvironment," published in the Journal for Immunotherapy of Cancer, reviews and summarizes the therapeutic response mechanisms of bexmarilimab in breast cancer models and further explores the decisive influence of macrophage subtypes within the TME on treatment outcomes. The text is coherent and logical, ending with a period in English.

Background Knowledge
Tumor-associated macrophages (TAMs) exhibit dual functionality in the tumor microenvironment (TME), both promoting anti-tumor immunity and supporting tumor growth and immune evasion. Bexmarilimab, a macrophage reprogramming antibody targeting Clever-1, has demonstrated clinical benefits in multiple solid tumors, though its efficacy mechanisms remain incompletely understood. This study utilizes a PDEC model from breast cancer patients combined with single-cell sequencing, spatial transcriptomics, and conditioned medium treatments to systematically investigate how TME regulates therapeutic responses to bexmarilimab. Results indicate that immunologically quiescent TMEs show greater sensitivity to bexmarilimab, while those with activated IFNγ signaling exhibit therapeutic resistance. Additionally, bexmarilimab activates B cell responses in adjacent normal tissues, independent of tumor-specific responses. These findings provide new molecular markers and therapeutic rationale for personalized immunotherapy strategies.

 

 

Research Methods and Experiments
This study constructed PDEC models using tumor tissues and adjacent normal tissues from breast cancer patients, analyzing bexmarilimab responses through RNA sequencing, multiplex cytokine detection, single-cell sequencing, and spatial transcriptomics. Researchers further evaluated the impact of Clever-1+ macrophage phenotypes and TME characteristics on treatment sensitivity using conditioned medium treatments, immune pathway enrichment analysis, and gene expression profile comparisons.

Key Conclusions and Perspectives

• The PDEC model validated gene signatures associated with bexmarilimab responses, including upregulation of APOL4, CXCL9, FCGR1A, FGL2, GBP5, HLA-DOA, SERPING1, and SLAMF7.
• Bexmarilimab activates pro-inflammatory immune pathways such as TNFα, IL2, and IFNγ signaling in immunologically quiescent TMEs but suppresses inflammatory responses in immunologically activated TMEs.
• Adjacent normal tissues under bexmarilimab treatment showed significant B cell pathway activation, independent of tumor responses.
• High proportions of IL4I1+ macrophages correlate with bexmarilimab resistance, suggesting their potential as predictive biomarkers for drug resistance.
• Clever-1+ macrophages in the TME exhibit substantial heterogeneity in phenotypes and developmental origins, with responses influenced by IFN signaling, spatial localization, and cellular origin within the TME.

Research Significance and Prospects
The study provides novel biomarkers and patient stratification strategies for clinical application of bexmarilimab, emphasizing the importance of pre-treatment immune microenvironment analysis. Future approaches may include personalized treatment designs based on TME features and exploration of combination therapies to overcome drug resistance.

 

Conclusion
This study systematically reveals the response heterogeneity of bexmarilimab under different TME contexts, demonstrating that tumor microenvironment and macrophage subtypes are key determinants of therapeutic efficacy. Through RNA sequencing and single-cell analyses, researchers established a predictive gene signature for treatment response and identified independent B cell activation mechanisms in adjacent normal tissues. These findings deepen understanding of macrophage-targeted immunotherapy while providing molecular evidence for future clinical trial designs. The ~300-word conclusion summarizes core discoveries, technical approaches, and translational potential, offering theoretical foundations and application directions for precision immunotherapy.

 

Jenna H Rannikko, Rita Turpin, Pia Boström, Ilkka Koskivuo, and Maija Hollmén. Macrophage sensitivity to bexmarilimab-induced reprogramming is shaped by the tumor microenvironment. Journal for Immunotherapy of Cancer.