Effects of microplastics on the colorectal tumor immune microenvironment and immunotherapy resistance via JAK–STAT–microbiota perturbation.

Abstract

e15731 Background: Microplastics (MPs) are pervasive environmental pollutants with rising human exposure. Although potential health effects have been recognized, their link to cancer remains poorly defined. The colorectum represents a primary absorption site for MPs, prompting investigation of their impact on colorectal cancer (CRC) progression and immunotherapy response. Methods: MPs were isolated and characterized from CRC tumor tissues and matched blood samples. Functional studies were conducted in murine CRC models to evaluate tumor progression, immune cell infiltration, gut microbiota alterations, and response to anti–PD-L1 therapy. Transcriptomic profiling and immune analyses were performed to elucidate underlying mechanisms. Results: MP exposure aggravated CRC progression and significantly reduced sensitivity to anti–PD-L1 therapy. Mechanistically, tumor-infiltrating MPs suppressed JAK-STAT signaling, downregulated IFN-γ, CXCL9, CXCL11, B2m, and H2-K1 expression, and reduced CD8⁺ and CD4⁺ T-cell infiltration, resulting in impaired antigen presentation and T-cell recruitment. MPs also induced gut microbiota dysbiosis that further contributed to immunotherapy resistance. Conclusions: MPs promote CRC immunotherapy resistance by altering the tumor immune microenvironment through disruption of the JAK-STAT–microbiota axis. These data highlight MPs as an unrecognized determinant of CRC immunotherapy outcomes and a potential modifiable environmental target amid rising global MP contamination.