Capsular polysaccharides from Cryptococcus neoformans suppress cancer through apoptosis and immune cell activation

Cryptococcus neoformans is an opportunistic fungus that causes severe systemic infections in immunocompromised hosts, particularly in individuals weakened by cancer or chemotherapy. Its main virulence factors, the capsular polysaccharides glucuronoxylomannan (GXM) and glucuronoxylomannogalactan (GXMGal), modulate immune responses during infection and exhibit potential antitumor effects by inducing apoptosis and modulating cellular recruitment. To investigate this dual role, systemic C. neoformans infection was evaluated in murine breast cancer (4 T1) and human lung cancer (A549) models. Although the infection worsened during tumor progression in mice, both purified polysaccharides (GXM and GXMGal) unexpectedly reduced solid tumor growth, while increasing ulcerations. Infected animals also displayed enhanced cytotoxic effector activity in the lungs and mammary tumors. Notably, solid tumors from infected mice showed higher PD-1 expression despite the reduced overall transcoelomic metastasis, suggesting infection restricts tumor dissemination independently of PD-1. Mechanistically, purified GXM and GXMGal directly induced apoptosis in 4 T1 and A549 cells in vitro while suppressing TGF-β production. In addition, the treatment with the polysaccharides also slowed down the growth of 4 T1 tumors, reflecting similar effects seen during infection. Critically, these polysaccharides enhanced recruitment of cytotoxic cells and monocytes to tumor sites and upregulated CCR7 expression in both leukocytes and tumors. Collectively, these findings demonstrate that C. neoformans polysaccharides antagonize tumor growth through direct cytotoxicity and immune modulation. Although infection exacerbates immunosuppression, isolated GXM and GXMGal emerge as dual-function therapeutics, enhancing antitumor immunity and inhibiting metastasis, highlighting their potential as microbial-derived agents for cancer immunotherapy.