Targeting the Tumor Microenvironment: A Review of Macrophage Immunotherapies Across Cancer Types

Abstract

Introduction: Macrophage immunotherapy is a promising approach to cancer treatment, leveraging the ability to target tumor-associated macrophages (TAMs) within the tumor microenvironment (TME). TAMs, often in an M2-like phenotype, contribute to immune evasion and tumor progression. This review synthesizes clinical trials of macrophage immunotherapy, including strategies to either deplete or reprogram M2-like TAMs to boost anti-tumor immunity.

Methods: This review systematically analyzes research conducted between January 2010 and April 2024. Literature was sourced from PubMed using terms like "macrophage cancer immunotherapy" and "tumor-associated macrophage immunotherapy." The studies reviewed include clinical trials and primary research involving TAM-targeting strategies across different cancer types.

Results: A total of 37 clinical trials were selected for this review, focusing on TAM-targeting therapies across 25 cancer types. The majority of studies examined solid tumors, including breast cancer, prostate cancer, and melanoma, alongside hematological malignancies. The therapeutic strategies investigated included monoclonal antibodies (mAbs), cytokine-based therapies, immune checkpoint inhibitors (ICIs), and oncolytic viruses. Notably, mAbs targeting CSF-1R showed a 45% increase in T-cell infiltration, and GM-CSF cytokine therapies successfully reprogrammed TAMs to an M1-like phenotype, enhancing anti-tumor immune responses. ICIs also demonstrated encouraging results, particularly in "hot" tumors, with progression-free survival (PFS) reaching up to 36 months.

Discussion: The reviewed trials underline the potential of TAM-targeting therapies in reshaping the TME and enhancing immune activation, especially in TAM-rich tumors. mAbs targeting CSF-1R and TREM2, along with GM-CSF reprogramming, were particularly effective in reducing TAM populations and promoting T-cell activity. Despite these promising outcomes, challenges remain due to the complexity of TAM biology and cancer-specific differences. Combination therapies, such as pairing CSF-1R inhibitors with ICIs, have shown potential to enhance efficacy by addressing multiple immune suppression mechanisms in the TME.

Conclusion: TAM-targeted therapies offer a promising approach in cancer immunotherapy by reprogramming the TME and restoring immune surveillance. However, challenges like TAM plasticity and tumor heterogeneity remain. Future trials should focus on refining combination therapies, standardizing biomarkers for patient stratification, and using advanced profiling technologies to enhance TAM-targeted treatments and improve outcomes.