Real-world evidence across diverse malignancies: Integrating immunotherapy efficacy, toxicity profiles, and predictive biomarkers

While immunotherapy has fundamentally transformed the clinical management of genitourinary (GU) and gastrointestinal (GI) malignancies, two critical mechanistic questions remain underexplored. First, why do certain tumors, prostate cancer in particular, remain “immunologically cold” and intrinsically resistant to immune-mediated killing despite the widespread success of immune checkpoint blockade across other cancer types? Second, why do immune-related adverse events (irAEs) manifest with distinct tissue- and organ-specific patterns, and what underlying immunological mechanisms drive this localized loss of tolerance? Elucidating the pathways behind both immune resistance and toxicity requires moving beyond descriptive clinical associations and delving deep into mechanistic tumor and tissue biology.To convert immunologically cold or resistant tumors into treatment-responsive malignancies, we must first understand tumor-intrinsic immune evasion. This requires decoding the molecular pathways that sustain an immunosuppressive microenvironment, the mechanisms driving cytotoxic lymphocyte exclusion, and the divergent evasion strategies employed across different cancers. In parallel, the mechanistic drivers of tissue- and organ-specific irAEs in this patient populations remain poorly characterized compared to more commonly studied tumors, limiting our ability to predict, prevent, and manage severe toxicity. Advancing both fields depends on uncovering causal immunological mechanisms, not merely observing clinical correlations.This Research Topic invites original research, mechanistic studies, and comprehensive reviews centered on the biology of immune evasion and irAE development in cancer immunotherapy. We also welcome complementary studies on biomarker discovery and tumor microenvironment (TME) characterization, provided they directly illuminate these core mechanistic questions.Topics of interest include, but are not limited to:• The "Cold" Phenotype: Molecular and cellular mechanisms maintaining immunologically cold microenvironments in resistant tumors.• Tumor-Intrinsic Evasion: Pathways specific to genitourinary (GU) and gastrointestinal (GI) malignancies, and their direct link to treatment resistance.• Mechanisms of Toxicity: Immunological drivers of irAE development, focusing on tissue- and organ-specific presentation patterns.• Therapeutic Overcoming: Rational strategies to dismantle immune evasion and convert cold tumors into immunotherapy-responsive phenotypes.• Mechanistic Biomarkers: Predictive biomarkers beyond PD-L1 supported by functional validation and directly tied to evasion or toxicity biology.• High-Resolution Profiling: Multi-omics, single-cell, or spatial transcriptomics of the tumor microenvironment (TME) utilized to uncover evasion mechanisms or predict irAE risk.By centering on the underlying immunology of both resistance and toxicity, this Research Topic aims to move cancer immunotherapy research beyond descriptive correlation and toward a comprehensive mechanistic understanding. Topic editors: Patrik Palacka, Marek Samec, Ondřej Fiala Source: https://www.frontiersin.org/research-topics/84825/real-world-evidence-across-diverse-malignancies-integrating-immunotherapy-efficacy-toxicity-profiles-and-predictive-biomarkers