Beyond oncogenesis: how pathogen-induced immune remodeling shapes tumor immune escape and immunotherapy resistance

Tumor immune escape limits the effectiveness of current anticancer treatments, particularly immune checkpoint blockade. Tumor-intrinsic alterations and host immune dysfunction have been widely studied. Yet the role of persistent pathogen infections as an external evolutionary force shaping tumor immunity remains poorly understood. Recent evidence indicates that oncogenic and tumor-associated pathogens both initiate malignant transformation and persistently remodel the tumor immune microenvironment. This remodeling fosters immune tolerance, tumor progression, and therapy resistance. In this review, we propose a pathogen-driven immune remodeling framework. This framework systematically explains how viruses, bacteria, fungi, and parasites regulate tumor immune escape through interconnected mechanisms. These mechanisms include immune checkpoint activation, recruitment and polarization of immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells, reprogramming of cytokine networks, metabolic adaptation, and disruption of antigen processing and presentation. Moreover, we highlight the dynamic interactions among pathogens, tumor cells, and the host immune system. These interactions create an infection-induced microenvironment marked by persistent inflammation and immune dysfunction. Importantly, we discuss how pathogen-mediated immune remodeling may contribute to resistance or attenuated responses to immunotherapy. We also explore new therapeutic strategies that target pathogen-related immune escape pathways, such as combination immunotherapy, microbial interventions, and personalized immunomodulation. This review integrates infectious factors into current tumor immunology models. It provides a conceptual framework for understanding tumor immune evolution and suggests new opportunities for precision immunotherapy in infection-associated and refractory cancers.