Candida albicans-Derived β-Glucan as a Novel Modulator of Tumor Microenvironment: Targeting Macrophage Polarization and Inducing Ferroptosis in Lung Cancer

Xiang He,1– 3,* Qin Ran,2,3,* Xiaolan Li,2,3,* Anying Xiong,2,3 Lei Zhang,2,3 Manling Jiang,2,3 Lingling Bai,2 Dan Peng,2 Junyi Wang,2,3 Baoqing Sun,1 Guoping Li1– 3 1National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, People’s Republic of China; 2Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, 610031, People’s Republic of China; 3Department of Respiration, Chengdu third People’s hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, 610031, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guoping Li; Baoqing Sun, Email [email protected]; [email protected]: Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and their polarization state significantly influences patient outcomes. This study investigates the inhibitory effects of β-glucan extracted from Candida albicans on lung cancer progression, focusing on its impact on TAM polarization and the induction of ferroptosis, a form of regulated cell death.Methods: Utilizing both in vivo animal models and in vitro cellular assays, we assessed the impact of β-glucan on tumor growth, cellular proliferation, and migration. We evaluated TAM polarization by analyzing the expression of M1 and M2 markers and identified differentially expressed genes (DEGs) related to ferroptosis. The role of ferroptosis in TAM polarization was further confirmed by assessing the protein levels of ACSL4 and GPX4, intracellular ferrous ion levels, and lipid peroxides.Results: β-glucan treatment significantly reduced tumor size and weight, along with cellular proliferation and migration, suggesting a potent suppressive effect on lung cancer cell growth. β-glucan promoted an M1-like phenotype in TAMs, as evidenced by increased CD86 expression and decreased CD206 expression, and modulated cytokine mRNA levels. RNA sequencing analysis post β-glucan treatment identified a substantial number of DEGs enriched in the ferroptosis pathway. The induction of ferroptosis by β-glucan was further confirmed through the significant upregulation of ACSL4 and downregulation of GPX4, alongside increased intracellular ferrous ion levels and lipid peroxides. The ferroptosis inhibitor Fer-1 abrogated these effects, highlighting the specificity of β-glucan-mediated polarization.Conclusion: These results collectively provide novel insights into the immunotherapeutic potential of β-glucan from Candida albicans and its role in modulating TAM polarization and lung cancer growth, offering a promising avenue for cancer treatment strategies.Keywords: β-glucan, lung cancer, TAMs, macrophage polarization, ferroptosis, C. albicans