Reprogramming Tumour-Associated Macrophages in Hepatocellular Carcinoma: From Molecular Mechanisms to Immunotherapeutic Strategies

Xinyu Song

doi:10.62051/ijphmr.v6n5.02

Authors

Xinyu Song

DOI:

https://doi.org/10.62051/ijphmr.v6n5.02

Keywords:

Tumour-associated macrophages, Hepatocellular carcinoma, Macrophage reprogramming, M1/M2 polarisation, Tumour microenvironment, CSF1R, Immune checkpoint blockade, CAR-macrophage

Abstract

Hepatocellular carcinoma (HCC) is still one of the top causes of cancer-related mortalities worldwide, and immunosuppressive tumour microenvironment (TME) is a key obstacle for effective therapy. Tumour-associated macrophages (TAMs) are one of the most abundant immune cells in the HCC TME and display a pro-tumourigenic character, which is related with immunosuppression, angiogenesis and resistance to systemic therapy. Reprogramming TAMs from M2-like pro-tumourigenic to an anti-tumour M1-like state has appeared as a viable therapeutic strategy. Herein we discuss the molecular pathways involved in TAM polarisation in HCC, including the CSF1R, PI3Kγ and NF-κB/STAT3 signalling pathways and review the therapeutic approaches targeting TAM re-programming including CSF1R inhibition, TLR agonists, combination with immune checkpoint blockade, CAR-macrophage engineering and nanoparticle-mediated delivery. We also highlight the clinical challenges of TAM-targeted therapy such as phenotypic plasticity and off-target toxicity, and markers for patient stratification.

References

[1] Cassetta, L., & Pollard, J. W. (2023). A timeline of tumour-associated macrophage biology. Nature Reviews Cancer, 23, 238–257. https://doi.org/10.1038/s41568-022-00547-1

[2] Sun, Z., Zhu, J., Zhou, Q., Chen, Y., Fu, J., Guo, L., Li, J., & Wang, X. (2023). Single-cell RNA sequencing reveals cell subpopulations in the tumour microenvironment contributing to hepatocellular carcinoma. Frontiers in Immunology, 14, 1169920.

[3] DeNardo, D. G., & Ruffell, B. (2019). Macrophages as regulators of tumour immunity and immunotherapy. Nature Reviews Immunology, 19(6), 369–382.

[4] Cassetta, L., & Pollard, J. W. (2018). Targeting macrophages: Therapeutic approaches in cancer. Nature Reviews Drug Discovery, 17(12), 887–904.

[5] Pan, X., Chang, D., Luo, L., Wang, X., & Jia, K. (2021). CSF1/CSF1R signaling inhibitor pexidartinib (PLX3397) reprograms tumor-associated macrophages and stimulates T-cell infiltration in the sarcoma microenvironment. Molecular Cancer Therapeutics, 20(9), 1806–1816.

[6] Kaneda, M. M., Messer, K. S., Ralainirina, N., Li, H., Leem, C. J., Gorjestani, S., Woo, G., Nguyen, A. V., Figueiredo, C. C., Foubert, P., Schmid, M. C., Pink, M., Winkler, D. G., Rausch, M., Palombella, V. J., Kutok, J., McGovern, K., Frazer, K. A., Wu, X., Karin, M., … Varner, J. A. (2016). PI3Kγ is a molecular switch that controls immune suppression. Nature, 539(7629), 437–442.

[7] Arlauckas, S. P., Garris, C. S., Kohler, R. H., Kitaoka, M., Cuccarese, M. F., Yang, K. S., Miller, M. A., Carlson, J. C., Freeman, G. J., Anthony, R. M., Weissleder, R., & Pittet, M. J. (2017). In vivo imaging reveals a tumour-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Science Translational Medicine, 9(389), eaal3604.

[8] Finn, R. S., Qin, M., Ikeda, M., Galle, P. R., Ducreux, M., Kim, T.-Y., Lim, H.-C., Breder, M., Merle, P., Kaseb, A. O., Li, D., Verret, I., Xu, D.-D., Hernandez, H., Liu, J., Huang, C., Mulla, A., Wang, Q., Empty, J. G., Cheng, A.-L., … Zhu, A. B. (2020). Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. New England Journal of Medicine, 382(20), 1894–1905.

[9] Guan, J., Wu, Y., Xia, Y., Liang, Z., Liao, W., Wang, Y., Xia, W., Zhang, Y., Wang, W., & Chen, F. (2024). GPC3-targeted CAR-M cells exhibit potent antitumor activity against hepatocellular carcinoma. Frontiers in Immunology, 15, 1428731.

[10] Chen, X., Zhang, Q., Li, J., Wang, M., Liu, C., & Xu, Z. (2014). Prognostic significance of tumour-associated macrophage infiltration in hepatocellular carcinoma: A meta-analysis. PLOS ONE, 9(12), e113677.

[11] Zhu, Q., Zhang, J., Yu, Y., Xu, C., & Huang, W. (2020). Tumour-associated macrophages correlate with sorafenib resistance in hepatocellular carcinoma via the HGF/c-Met pathway. Cell Communication and Signaling, 18(1), 188.

[12] Anfray, C., Ummarino, A., Torres-Andon, F., & Allavena, P. (2020). Current strategies to target tumour-associated macrophages to improve anti-tumour immune responses. Cells, 9(1), 46. https://doi.org/10.3390/cells9010046

[13] Leone, R. D., & Powell, J. D. (2020). Metabolism of immune cells in cancer. Nature Reviews Cancer, 20(9), 516–531.

[14] Mantovani, Y., Biswas, S. K., Galdiero, P. B., Sica, A., & Locati, M. (2012). Macrophage plasticity and interaction with lymphocyte subsets. Cancer Immunology, Immunotherapy, 61(2), 170–188.

[15] Huang, B., Pan, P., Li, Q., Shen, A., Lian, H., Wan, D., Zhuo, J. L., & Gu, Q. (2006). Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumour-induced T regulatory cells and T-cell anergy in tumour-bearing host. Cancer Research, 66(2), 1123–1131.