From infection to cholangiocarcinoma: Why opisthorchiids break these rules

Helminth infections are among the most prevalent causes of chronic inflammation in humans, but only a small subset of these infections is causally linked to cancer. This discrepancy challenges the long-standing assumption that chronic inflammation is intrinsically carcinogenic and suggests that additional constraints govern inflammation-driven tumorigenesis in parasitic diseases.

This review aims to explain why most helminths fail to induce malignancy despite long-term inflammatory host responses, and why opisthorchiid liver trematodes represent a rare and informative exception. We seek to integrate primary experimental, epidemiological, and pathological evidence into a unified conceptual settings applicable to helminth-associated cancers.

We introduce the concept of a "pro-oncogenic inflammation threshold," proposing that carcinogenesis emerges only when multiple dimensions converge simultaneously: sustained inflammatory intensity and quality, prolonged exposure, genotoxic stress, tissue-specific vulnerability, and permissive environmental cofactors. Most helminths remain below this threshold because of evolutionary selection that favors host survival, the absence of direct genotoxins, and effective immunoregulatory mechanisms. In contrast, opisthorchiids exceed this threshold through chronic mechanical injury to bile ducts, secretion of genotoxic and mitogenic metabolites, synergy with dietary nitrosamines, perturbation of the biliary microbiome, and failure of reparative homeostasis.

Helminth-induced cancers represent a neglected category of tropical disease that remains poorly integrated into global oncology strategies because of disciplinary fragmentation and a mutation-centric cancer paradigm. Setting helminth-associated carcinogenesis in a One Health context highlights actionable prevention opportunities at the human-animal-environment interface. Chronic helminth-induced inflammation is therefore a conditional, rather than universal, driver of cancer.