M2 Macrophage Polarization: Signaling Pathways, Metabolic Reprogramming, and Targeting Strategies in Cancer Therapy

Authors

  • Xianyue Guo

DOI:

https://doi.org/10.61173/0yb1va84

Keywords:

Macrophage polarization, Signaling path-ways, Metabolic reprogramming, Exosomes, Targeted therapy

Abstract

In the microenvironment of the tumor, there are two subpopulations of tumor associated macrophages (TAMs) with opposite functions: proinflammatory M1 macrophages and immunosuppressive M2 macrophages. Among them, M2-like macrophages' primary function in TME is inhibiting immune response and promoting tumor progression. In order to combat the immunosuppressive effect of M2-like TAMs, this article examines the variables linked to TAM polarization as well as possible tactics for directing TAM repolarization to the M1 pro-inflammatory phenotype for cancer treatment. This article systematically expounds how to intervene tumor progression by targeting the polarization of M2 macrophages, including: 1) An outline of M2 macrophages' function in the TME; 2) The signaling pathways related to TAM polarization (such as STAT family signaling pathway, PI3K/Akt signaling pathway), the reprogramming of cellular metabolic pathways, and the involvement of tumor derived exosomal ncRNA were introduced; 3) A variety of methods to target TAM's orientation to the pro-inflammatory M1 phenotype are discussed, such as signaling pathway inhibition, metabolic intervention, exosomes and other targeting strategies. Therefore, targeting M2 macrophage polarization is an effective strategy to reverse tumor progression, providing a new perspective for cancer therapy.

References

[1] Gao J, Liang Y, and Wang L., “Shaping polarization of tumor-associated macrophages in cancer immunotherapy,” Front. Immunol., vol. 13, Jun. 30, 2022, Art. no. 888713.

[2] Rodriguez-Garcia A., Lynn R. C., Poussin M., Eiva M. A., Shaw L. C., O’Connor R. S., Minutolo N. G., Casado-Medrano V., Lopez G., Matsuyama T., and Powell D. J. Jr., “CAR-T cellmediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy,” Nat. Commun., vol. 12, no. 1, Feb. 9, 2021, Art. no. 877.

[3] Boutilier A. J. and Elsawa S. F., “Macrophage polarization states in the tumor microenvironment,” Int. J. Mol. Sci., vol. 22, no. 13, Jun. 29, 2021, Art. no. 6995.

[4] Huffaker T. B., Ekiz H. A., Barba C., Lee S. H., Runtsch M. C., Nelson M. C., Bauer K. M., Tang W. W., Mosbruger T. L., Cox J. E., Round J. L., Voth W. P., and O’Connell R. M., “A Stat1 bound enhancer promotes Nampt expression and function within tumor associated macrophages,” Nat. Commun., vol. 12, no. 1, May 11, 2021, Art. no. 2620.

[5] Zhong Q., Fang Y., Lai Q., Wang S., He C., Li A., Liu S., and Yan Q., “CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling,” J. Exp. Clin. Cancer Res., vol. 39, no. 1, Jul. 11, 2020, Art. no. 132.

[6] Yao A., Liu F., Chen K., Tang L., Liu L., Zhang K., Yu C., Bian G., Guo H., Zheng J., Cheng P., Ju G., and Wang J., “Programmed death 1 deficiency induces the polarization of macrophages/microglia to the M1 phenotype after spinal cord injury in mice,” Neurotherapeutics, vol. 11, no. 3, pp. 636–650, Jul. 2014.

[7] Wang L., Li S., Luo H., Lu Q., and Yu S., “PCSK9 promotes the progression and metastasis of colon cancer cells through regulation of EMT and PI3K/AKT signaling in tumor cells and phenotypic polarization of macrophages,” J. Exp. Clin. Cancer Res., vol. 41, no. 1, Oct. 14, 2022, Art. no. 303.

[8] Li M., Li M., Yang Y., Liu Y., Xie H., Yu Q., Tian L., Tang X., Ren K., Li J., Zhang Z., and He Q., “Remodeling tumor immune microenvironment via targeted blockade of PI3K-γ and CSF-1/CSF-1R pathways in tumor associated macrophages for pancreatic cancer therapy,” J. Control. Release, vol. 321, pp. 23–35, May 10, 2020.

[9] Xiao S., Qi M., Zhou Q., Gong H., Wei D., Wang G., Feng Q., Wang Z., Liu Z., Zhou Y., and Ma X., “Macrophage fatty acid oxidation in atherosclerosis,” Biomed. Pharmacother., vol. 170, Jan. 2024, Art. no. 116092.

[10] Zhao S., Mi Y., Guan B., Zheng B., Wei P., Gu Y., Zhang Z., Cai S., Xu Y., Li X., He X., Zhong X., Li G., Chen Z., and Li D., “Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer,” J. Dean&Francis ISSN 2959-409X Hematol. Oncol., vol. 13, no. 1, Nov. 19, 2020, Art. no. 156.

[11] Deng C., Huo M., Chu H., Zhuang X., Deng G., Li W., Wei H., Zeng L., He Y., Liu H., Li J., Zhang C., and Chen H., “Exosome circATP8A1 induces macrophage M2 polarization by regulating the miR-1-3p/STAT6 axis to promote gastric cancer progression,” Mol. Cancer, vol. 23, no. 1, Mar. 8, 2024, Art. no. 49.

[12] Glaviano A., Foo A. S. C., Lam H. Y., Yap K. C. H., Jacot W., Jones R. H., Eng H., Nair M. G., Makvandi P., Geoerger B., Kulke M. H., Baird R. D., Prabhu J. S., Carbone D., Pecoraro C., Teh D. B. L., Sethi G., Cavalieri V., Lin K. H., Javidi-Sharifi N. R., Toska E., Davids M. S., Brown J. R., Diana P., Stebbing J., Fruman D. A., and Kumar A. P., “PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer,” Mol. Cancer, vol. 22, no. 1, Aug. 18, 2023, Art. no. 138.

[13] Liu N., Rowley B. R., Bull C. O., Schneider C., Haegebarth A., Schatz C. A., Fracasso P. R., Wilkie D. P., Hentemann M., Wilhelm S. M., Scott W. J., Mumberg D., and Ziegelbauer K., “BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models,” Mol. Cancer Ther., vol. 12, no. 11, pp. 2319– 2330, Nov. 2013.

[14] Steggerda S. M., Bennett M. K., Chen J., Emberley E., Huang T., Janes J. R., Li W., MacKinnon A. L., Makkouk A., Marguier G., Murray P. J., Neou S., Pan A., Parlati F., Rodriguez M. L. M., Van de Velde L. A., Wang T., Works M., Zhang J., Zhang W., and Gross M. I., “Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment,” J. Immunother. Cancer, vol. 5, no. 1, Dec. 19, 2017, Art. no. 101.

[15] Zhu Y., Zhang S., Sun J., Wang T., Liu Q., Wu G., Qian Y., Yang W., Wang Y., and Wang W., “Cigarette smoke promotes oral leukoplakia via regulating glutamine metabolism and M2 polarization of macrophage,” Int. J. Oral Sci., vol. 13, no. 1, Aug. 9, 2021, Art. no. 25.

[16] Xun J., Du L., Gao R., Shen L., Wang D., Kang L., Chen C., Zhang Z., Zhang Y., Yue S., Feng S., Xiang R., Mi X., and Tan X., “Cancer-derived exosomal miR-138-5p modulates polarization of tumor-associated macrophages through inhibition of KDM6B,” Theranostics, vol. 11, no. 14, pp. 6847–6859, May 3, 2021.

[17] Chi X., Ding B., Zhang L., Zhang J., Wang J., and Zhang W., “lncRNA GAS5 promotes M1 macrophage polarization via miR-455-5p/SOCS3 pathway in childhood pneumonia,” J. Cell. Physiol., vol. 234, no. 8, pp. 13242–13251, Aug. 2019.

[18] Zhang Y., Bi J., Huang J., Tang Y., Du S., and Li P., “Exosome: A review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications,” Int. J. Nanomedicine, vol. 15, pp. 6917–6934, Sep. 22, 2020.

[19] Finan J. M., Guo Y., Goodyear S. M., and Brody J. R., “Challenges and opportunities in targeting the complex pancreatic tumor microenvironment,” JCO Oncol. Adv., vol. 1, Dec. 18, 2024, Art. no. e2400050.

[20] Dussold C., Zilinger K., Turunen J., Heimberger A. B., and Miska J., “Modulation of macrophage metabolism as an emerging immunotherapy strategy for cancer,” J. Clin. Invest., vol. 134, no. 2, Jan. 16, 2024, Art. no. e175445.

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Published

2025-08-26