Beyond molecular mimicry: immune memory as the missing dimension of cancer immune surveillance

Molecular mimicry has emerged as a key mechanism linking microbial immunity to cancer immune surveillance, with growing evidence that microbial antigens can elicit T-cell responses cross-reactive with tumor-associated antigens. However, current interpretations remain largely antigen-centered, emphasizing structural similarities between individual epitopes. Here, we propose a broader conceptual framework in which molecular mimicry is viewed as the functional manifestation of a lifelong, cross-reactive memory T-cell repertoire shaped by infections, vaccination, microbiota, and environmental antigenic exposures. In this perspective, the critical determinant of tumor recognition is not simply antigen similarity, but whether the host immune repertoire has previously acquired the capacity to recognize the structural antigenic space occupied by tumor antigens. This shift moves the focus from the tumor to the host, positioning immune history as a central determinant of cancer immune surveillance. We discuss how this framework integrates diverse observations in cancer immunology and suggest that exploiting pre-existing immune memory may guide the development of improved biomarkers, cancer vaccines, and next-generation immunotherapies.