From telomere dysfunction to seno-antigen selection: a conceptual framework and route-specific evidence appraisal for senolytic immunotherapy.
Niazi Sarfaraz K SK
Cellular senescence causally contributes to age-related and chronic diseases, rendering the targeted immune clearance of pathological senescent cells a promising therapeutic avenue. Progress remains limited by heterogeneity across cell lineages, tissues, inducing stressors, and temporal factors. As antigen expression alone does not ensure immune accessibility, functional recognition, or safety for healthy tissues, these aspects warrant thorough evaluation. A conceptual framework is proposed, distinct from a validated or implementable algorithm, for identifying and prioritizing senescence-associated antigens. This framework requires four criteria that a single candidate antigen must meet within the same cellular context: persistent pathological senescence, immune accessibility via a confirmed surface antigen or naturally presented human leukocyte antigen (HLA) peptide, modality-appropriate functional immune recognition, and exclusion from vital healthy or beneficially senescent states. The mechanistic origin, such as telomere dysfunction, serves as an optional stratification axis that defines coherent subsets rather than a universal prerequisite; data lacking matched telomere and antigen information in the same cells remain unverified. The process distinguishes target nomination from product validation: evidence of recognition in a single modality, such as chimeric antigen receptor (CAR) targeting of a surface antigen, does not confirm validation for alternatives like peptide vaccines. Application of the framework to urokinase-type plasminogen activator receptor (uPAR) and glycoprotein nonmetastatic melanoma protein B (GPNMB) indicates that neither candidate currently meets all criteria, and the telomere axis remains untested for both. Given that multivalent vaccination elicits immunity against each component independently, combining candidates that fail individual criteria risks amplifying liabilities rather than ensuring intersectional specificity. This outcome would require an engineered AND-gated recognition system, where the capitalized operators AND, OR, and NOT denote Boolean logic gates rather than emphasis. The framework remains in the validation phase. Each criterion receives an ordinal grade, a non-compensatory decision rule, a route-specific ligand-density window that sets the quantitative condition for recognition and healthy-cell sparing, and a predefined seven-compartment counter-screening panel. Recognition architectures are formally compared, and a pre-registered benchmarking study with specified falsification criteria is outlined as the framework's validation test.