The Genetic Firewall Against Cellular Parasitism: Evolution of Allorecognition and the Limits of Cancer Transmissibility

Multicellular individuality depends upon constraints that limit the establishment and evolutionary success of genetically foreign cellular lineages. Naturally transmissible cancers expose the permeability of these constraints because malignant cells can propagate between unrelated organisms. Although ecological barriers to transmission, allorecognition and host–parasite genotype-by-genotype interactions are established evolutionary concepts, their integration into a stage-resolved account of somatically derived cellular parasitism remains incomplete. This review critically synthesises evidence from transmissible cancers in dogs, Tasmanian devils, bivalves and freshwater catfish alongside genetically regulated cellular recognition in colonial invertebrates. Historical experimental transmission in soft-shell clams, recent environmental-survival studies, comparative tumour genomics and contemporary host population-genetic responses provide complementary evidence. A Genetic Firewall Framework is proposed as a restricted application of established host–parasite compatibility theory to clonally transmissible malignant cells. It distinguishes exposure, viable-cell entry, recognition-mediated elimination, post-entry niche compatibility and onward transmission. An explicit recipient-genotype-by-clone-genotype establishment model is linked to host fitness and malignant-lineage frequency dynamics. The primary empirical prediction concerns reproducible, stage-specific compatibility effects, with susceptibility-rank reversal representing a particularly discriminating but non-essential interaction pattern. A falsification-oriented programme centred on Mya arenaria separates inherited resistance from tumour-intrinsic attenuation, environmental confounding and phylogenetic pseudoreplication. The framework neither assumes homologous recognition systems across taxa nor claims an established universal antitumour mechanism. Its value lies in determining when genetic compatibility explains cellular parasitism and when simpler ecological or physiological explanations prevail.