Benjamin Galison

Background: Cancer is not simply a genetic disease.¹ The tumor microenvironment (TME) displays significant modifications, allowing the tumor to hijack innate immune system targeting, promote angiogenesis, modify the extracellular matrix, and alter metabolism.¹ Understanding the TME is critical to developing cancer therapies, as 90-95% of cancers are tumor-derived.¹ The TME contains tumor associated macrophages (TAMs) that predominate in the M2 phenotype. In breast cancer, for example, M2 macrophages can comprise 50% of tumor mass.² IL-4 is a cytokine that activates the JAK1/STAT6 pathway in macrophage precursors, driving the cells into the M2 pro-tumor phenotype.^1,3 JAK1/STAT6 signaling transcribes ARG-1.⁴ Arginase suppresses CD8+ T cells in the TME by cleaving arginine into ornithine and urea.⁴ The suppression of CD8+ T cells ultimately results in immune evasion and tumor growth. Targeting any of the steps of this pathway could lead to novel therapies.

Objective: The objective of this review is to examine a mechanism by which macrophages in the TME are induced into the pro-tumor M2 phenotype, and how the M2 phenotype promotes tumor growth.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2025 using the following keywords: “tumor microenvironment”, “M2 macrophages”, “IL-4″, ” JAK1/STAT6″,
ARG-1”.

Results: Studies indicate the role of IL-4 as a driver of M2 macrophage differentiation in the TME.⁴ This cytokine activates the JAK1/STAT6 signaling pathway which drives the expression of Arginase in mice. Using western blotting, JAK1 and STAT6 were expressed upon IL-4 induction in vitro.⁵ The macrophages demonstrated an M2 phenotype subsequently as expressed via fluorescence microscopy. In addition to driving M2 differentiation, JAK1/STAT6 signaling induces expression of anti-inflammatory cytokines such as IL-10, TGF-Beta, VEGF, and more.⁴ Murine cells were isolated in vitro and the anti-inflammatory cytokines were quantified using reverse transcriptase (RT) polymerase chain reaction (PCR).⁴ Inflammation is an immune response that is necessary for cancer suppression. By releasing these anti-inflammatory cytokines, the M2 macrophages assist the cancer cells in immune evasion. Additionally, JAK1/STAT6 signaling promotes Arginase expression, as demonstrated by human pancreatic ductal adenocarcinomas.⁶ Control (non-cancerous) displayed significantly lower arginase levels in macrophages with p=0.0027.⁶ The significance of arginase is that arginine is an amino acid essential for CD8+ T cell survival.⁷ M2 macrophages increase arginase in the TME, which decreases arginine, and suppresses CD8+ T cells, creating a TME suitable for immune evasion and cancer growth. Novel therapies such as Nab-palcitaxel have been used as an attempt to inhibit this pathway by IL4-R antagonism. The gap in effectiveness continues to be rooted in drug organ specificity, since components in this pathway are ubiquitous systemically in normal functioning cellular environments.⁸

Conclusions: M2 macrophages in the TME promote a pro-tumor state through various signaling pathways.¹ One of which is through IL-4, JAK1/STAT6, and Arginase.^1,2,3,4 These components reduce inflammation in the TME and suppress CD8+ T cells which are critical for immune targeting of cancer cells.⁷ M2 to M1 reeducation holds promise to inhibit this signaling pathway to inhibit tumor growth. Therapies will need to overcome the issue of targeting cells with high specificity but have the potential to slow tumor growth.

Works Cited:

1. de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell. Mar 13 2023;41(3):374-403. doi:10.1016/j.ccell.2023.02.016
2. Wang S, Liu G, Li Y, Pan Y. Metabolic Reprogramming Induces Macrophage Polarization in the Tumor Microenvironment. Front Immunol. 2022;13:840029. doi:10.3389/fimmu.2022.840029
3. Chen S, Saeed A, Liu Q, et al. Macrophages in immunoregulation and therapeutics. Signal Transduct Target Ther. May 22 2023;8(1):207. doi:10.1038/s41392-023-01452-1
4. Endo TH, Mizuno N, Matsuda S, Shiga S, Yanagawa Y. Synergy of interleukin-4 and interferon-gamma in arginase-1 production in RAW264.7 macrophages. Asian Pac J Allergy Immunol. Dec 2023;41(4):379-388. doi:10.12932/AP-160221-1067
5. He Y, Gao Y, Zhang Q, Zhou G, Cao F, Yao S. IL-4 Switches Microglia/macrophage M1/M2 Polarization and Alleviates Neurological Damage by Modulating the JAK1/STAT6 Pathway Following ICH. Neuroscience. Jun 15 2020;437:161-171. doi:10.1016/j.neuroscience.2020.03.008
6. Menjivar RE, Nwosu ZC, Du W, et al. Arginase 1 is a key driver of immune suppression in pancreatic cancer. Elife. Feb 2 2023;12doi:10.7554/eLife.80721
7. Tharp KM, Kersten K, Maller O, et al. Tumor-associated macrophages restrict CD8(+) T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment. Nat Cancer. Jul 2024;5(7):1045-1062. doi:10.1038/s43018-024-00775-4
8. Vadevoo SMP, Kang Y, Gunassekaran GR, et al. IL4 receptor targeting enables nab-paclitaxel to enhance reprogramming of M2-type macrophages into M1-like phenotype via ROS-HMGB1-TLR4 axis and inhibition of tumor growth and metastasis. Theranostics. 2024;14(6):2605-2621. doi:10.7150/thno.92672