Immune Absence as a Proposed Framework for Delayed Relapse After Curative-Intent Treatment in Human...

Delayed relapse after curative-intent treatment remains difficult to explain and predict in human papillomavirus (HPV)-associated cervical cancer, including after periods of sustained remission with undetectable circulating tumor DNA (ctDNA) or circulating HPV DNA. This limitation of tumor-centered surveillance demands the evaluation of immune parameters alongside tumor-derived biomarkers. We propose "immune absence" as a hypothesis-generating, operational framework referring to the sustained reduction or non-persistence of pre-specified tumor-reactive T-cell receptor (TCR) clonotypes in serial peripheral blood samples, obtained during minimal residual disease states in which antigen exposure may be limited or intermittent. We hypothesize that this longitudinal pattern may precede molecular or clinical evidence of relapse in a subset of patients and coexist with established mechanisms, such as tumor evolution, immune escape, T-cell dysfunction, and therapeutic resistance. Integrating serial ctDNA or circulating HPV DNA measurements with tumor-reactive TCR clonotype dynamics may provide complementary information on residual tumor burden and the persistence of circulating tumor-reactive T-cell responses. Peripheral blood TCR non-detection does not establish complete loss of anti-tumor immunity and may reflect compartmentalized immunity, clonal replacement, antigenic evolution, or assay limitations. Prospective longitudinal studies are required to establish the prognostic value of this framework before clinical use.