On Central Immunological Tolerance Defects and Oncogenesis: A Closed-Loop Deduction Based on the X+n/X−n Thymic Selection and Immune Surveillance Model

Abstract

Traditional oncology often posits environmental exposure and gene mutations as the primary causal factors in cancer development. However, epidemiological paradoxes—such as the high cancer incidence in countries with pristine natural environments, significant age-standardized incidence variations across ethnicities, and the rapid outbreak of multiple primary cancers following organ transplantation—reveal that environmental factors serve merely as random triggers. In contrast, the host's intrinsic immune surveillance and rejection capacity constitute the ultimate determinant of tumor outcome. Drawing upon the mechanisms of positive and negative selection during thymic maturation, this paper proposes the X+n/X−n Thymic TCR Clonal Deletion Hypothesis. We postulate that ethnicity- or individual-specific Human Leukocyte Antigen (HLA) gene polymorphisms lead thymic Antigen-Presenting Cells (APCs) to overpresent or aberrantly present specific self or embryonic antigens (X+n). Consequently, specific T-cell clones capable of recognizing these mutation targets are induced to undergo apoptosis during central tolerance (X−n). This blind spot in the peripheral T-cell receptor (TCR) repertoire (n) prevents the immune system from silently clearing single-cell transformed lesions triggered by environmental factors, enabling tumor escape. Integrating the fundamental logic of animal tumor modeling with the clinical breakthroughs of Moderna’s mRNA personalized cancer vaccines (PCVs), this study establishes a comprehensive closed-loop logic connecting molecular development, epidemiology, and frontier cancer immunotherapy.