Megan Hansen

Background: Obesity is chronic disease characterized by excess adipose tissue.1 Adipose tissue is an endocrine organ that secretes bioactive molecules can influence the function of other cells and organs.^1,2 Individuals with obesity display abnormal adipocyte biomolecule expression that has been linked to the development of cancer, among which is breast cancer.^2,3,4,5,6 Normal breast tissue contains significant numbers of immune cells, one of the most prominent being CD8+ T cells.⁷ Higher amounts of tumor-infiltrating CD8+ T cells are associated with a better cancer prognosis, and it is hypothesized that obesity suppresses CD8+ T cells via dysregulation of bioactive molecule secretion, leading to an immunosuppressive state that permits breast cancer development and progression.^2,7 Recent studies have highlighted a variety of mechanisms that are altered in obesity-associated breast cancer, but careful analysis and comparison of the research indicates that IL6 and CXCL1, expressed by adipocytes and breast cancer cells respectively, are drivers of the immunosuppressive environment.

Objective: Explore the mechanisms driving obesity-induced CD8+ T cell immunosuppression in the breast cancer environment.

Search Methods: Utilizing the PubMed database, a search was conducted using papers published from 2018-2026 using the following terms: “obesity,” “breast cancer,” breast carcinogenesis,” and “CD8+ T cell.”

Results: Studies demonstrated that tumors isolated from obese mice display lower percentages of tumor-infiltrating CD8+ T cells, and increased numbers of myeloid derived suppressor cells (MDSCs).^3,4 MDSCs mediate CD8+ T cell death in BC tumors by acting as the major source of FasL – a ligand that binds to the Fas receptor on CD8+ T cells, which is also upregulated in obesity, and initiates apoptosis in CD8+ T cells.⁴ CXCL1 is a chemokine that acts as an MDSC chemotactant by binding to CXCR2 on MDSCs, resulting in increased MDSCs in regions where CXCL1 expression is upregulated.⁴ CXCL1 was significantly increased in tumors derived from obese mice, and is a driver of the increased levels of MDSCs in obese mouse tumors.⁴ Co-culture of breast cancer cells and adipocytes showed that CXCL1 is secreted by breast cancer cells and binds to CXCR2 on adipocytes.⁸ Activation of CXCR2 results in increased expression of IL6 by adipocytes, which in turn binds to IL6R on breast cancer cells and upregulates the expression of CXL1.⁸

Conclusions: Obesity increases breast cancer risk and cultivates an immunosuppressive tumor microenvironment. One of the mechanisms identified in obesity-driven breast cancer progression occurs because of a positive feedback loop between adipocytes and breast cancer cells. Elevated levels of CXCL1, secreted by breast cancer cells and upregulated by adipocyte IL6 excretion, contribute to the immunosuppressive environment of obesity-associated breast cancer. CXCL1 recruits MDSCs to the tumor which utilize Fas/FasL interactions to cause CD8+ T cell death. The decrease in CD8+ T cells results in inhibited antigen presentation and overall anti-tumor response by the immune system, resulting in more aggressive tumor progression and poorer outcomes. Future research can build upon these findings by targeting the IL6-CXCL1 adipocyte-breast cancer cell feedback loop to inhibit cancer progression and improve outcomes in individuals with obesity-driven cancer.

Works Cited:

1. Agurs-Collins T, Ross SA, Dunn BK. The Many Faces of Obesity and Its Influence on Breast Cancer Risk. Front Oncol. 2019;9:765. Published 2019 Sep 4. doi:10.3389/fonc.2019.00765
2. Abdulla A, Sadida HQ, Jerobin J, et al. Unraveling molecular interconnections and identifying potential therapeutic targets of significance in obesity-cancer link. J Natl Cancer Cent. 2024;5(1):8-27. Published 2024 Nov 28. doi:10.1016/j.jncc.2024.11.001
3. Núñez-Ruiz A, Sánchez-Brena F, López-Pacheco C, Acevedo-Domínguez NA, Soldevila G. Obesity modulates the immune macroenvironment associated with breast cancer development. PLoS One. 2022;17(4):e0266827. Published 2022 Apr 26. doi:10.1371/journal.pone.0266827
4. Gibson JT, Orlandella RM, Turbitt WJ, et al. Obesity-Associated Myeloid-Derived Suppressor Cells Promote Apoptosis of Tumor-Infiltrating CD8 T Cells and Immunotherapy Resistance in Breast Cancer. Front Immunol. 2020;11:590794. Published 2020 Oct 6. doi:10.3389/fimmu.2020.590794
5. Kuziel G, Moore BN, Haugstad GP, Xiong Y, Williams AE, Arendt LM. Alterations in the mammary gland and tumor microenvironment of formerly obese mice. BMC Cancer. 2023;23(1):1183. Published 2023 Dec 1. doi:10.1186/s12885-023-11688-3
6. Zhang C, Yue C, Herrmann A, et al. STAT3 Activation-Induced Fatty Acid Oxidation in CD8+ T Effector Cells Is Critical for Obesity-Promoted Breast Tumor Growth. Cell Metab. 2020;31(1):148-161.e5. doi:10.1016/j.cmet.2019.10.013
7. Goff SL, Danforth DN. The Role of Immune Cells in Breast Tissue and Immunotherapy for the Treatment of Breast Cancer. Clin Breast Cancer. 2021;21(1):e63-e73. doi:10.1016/j.clbc.2020.06.011
8. Ruan GT, Zhu LC, Xie HL, et al. Adipocyte-derived IL6 and triple-negative breast cancer cell-derived CXCL1 co-activate STAT3/NF-κB pathway to mediate the crosstalk between adipocytes and triple-negative breast cancer cells. Cell Death Discov. 2025;11(1):395. Published 2025 Aug 21. doi:10.1038/s41420-025-02713-4