Heliang Li,1,2,* Xinyan Liang,1,2,* Jiafan Ma,1,2,* Qiang Liu,1,2 Ying Lin,3 Junpeng Tang,4 Zefang Ren,5 Zhuozhi Liang1,2,6 

1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China; 2Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China; 3Breast Disease Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 4Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 5The School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China; 6Zenith Institute of Medical Sciences, Guangzhou, Guangdong, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Zhuozhi Liang; Zefang Ren, Email liangzhzh6@mail2.sysu.edu.cn; renzef@mail.sysu.edu.cn

Purpose: Previous studies have reported that infection-induced fever is associated with improved breast cancer prognosis, potentially through the modulation of cytokines. However, the key cytokines and the underlying mechanisms through which fever exerts its anti-tumor effects remain unclear.
Patients and Methods: A total of 794 breast cancer patients were recruited between 2008 and 2017, with follow-up extending until October 31st, 2023. Infection-induced fever was assessed using questionnaires, while a multiplex assay evaluated a panel of 27 cytokines. The mediation effects of various cytokines were analyzed through model-based causal mediation analysis. Additionally, we explored modifications to these mediation effect by examining interactions among the cytokines themselves as well as their interactions with infection-induced fever. Bioinformatic analyses were conducted to elucidate the biological pathways mediating infection-induced fever.
Results: The relationship between infection-induced fever and improved breast cancer prognosis was mediated by a decrease in interleukin-8 (IL-8) levels. Furthermore, our findings revealed that the downregulation of IL-8, which mediates the beneficial effects of fever, was antagonized by IL-2, IL12p70 and IL-7. By intersecting the biological pathways influenced by IL-8, alongside those affected by IL-2, IL12p70, or IL-7, we found that these latter cytokines antagonized the mediation effects of IL-8 via regulating critical pathways such as neutrophil degranulation, extracellular matrix organization and asparagine N-linked glycosylation.
Conclusion: Infection-induced fever may improve breast cancer prognosis through IL-8 downregulation and the mediation mechanisms may be involved in neutrophil degranulation, extracellular matrix organization and asparagine N-linked glycosylation. Such findings not only provide valuable insights into effectively managing febrile responses for breast cancer patients, but also underscore the therapeutic potential of cytokines in breast cancer patients.

Keywords: infection-induced fever, breast cancer, prognosis, cytokines, IL-8