A Latent Inflammatory Tissue-State Variable Mechanistically Links Radiotherapy-Induced Immune Remodeling to Recurrent Tumor Permissiveness.

Triple-negative breast cancer recurrence following radiotherapy is associated with a microenvironment characterized by immune dysfunction and persistent inflammation. We developed an experimentally constrained agent-based model to investigate how transient immune remodeling becomes a persistent recurrence-permissive tissue state. The model reproduced experimentally observed macrophage recruitment and phenotype dynamics but demonstrated that recurrent recruitment, impaired inflammatory resolution, and adaptive immune bias were insufficient to reproduce the recurrent macrophage ecology. We therefore introduced recurrence-associated microenvironmental inflammation (RAMI), a latent tissue-state variable representing accumulated unresolved inflammatory remodeling. Coupling RAMI to the emergence of experimentally constrained interleukin-6 signaling generated tissue-to-cell feedback that reinforced recurrence-associated macrophage phenotypes and increased tumor establishment, supporting inflammatory tissue memory as a mechanistic intermediary between transient immune perturbation and persistent recurrent tumor permissiveness.