Parasite-Associated Cancers as Predicted Checkpoint Inhibitor Responders: A Mechanistic Hypothesis with Evidence from CCA, EBV-Positive NHL, and Bladder Cancer Trials

Background. Checkpoint inhibitor trials — the dominant advance in solid tumour oncology over the past decade — have been conducted almost exclusively in populations from high-income, helminth-naive settings. Patients from sub-Saharan Africa, Egypt, South and Southeast Asia, and other helminth-endemic regions, where parasite-associated cancers are most prevalent, are systematically under-represented. This creates a specific unexamined question: are parasite-associated cancers actually better checkpoint inhibitor responders than histologically matched cancers in helminth-naive Western populations? Hypothesis. Chronic helminth infection generates two independent features that are both established positive predictors of checkpoint inhibitor response: (1) Th2/Treg immune polarisation driving elevated PD-L1 expression on tumour cells; and (2) elevated tumour mutational burden (TMB) from chronic genotoxin exposure (notably N-nitroso compounds from schistosomal metabolism and related parasite-driven inflammation). Both mechanisms independently favour response to anti-PD-1/PD-L1 therapy if checkpoint blockade successfully restores CD8⁺ cytotoxic T lymphocyte (CTL) activity. Evidence....