BEFORE THE TUMOUR: IMMUNE REPERTOIRE ARCHITECTURE AND THE CEILING OF CANCER IMMUNE SURVEILLANCE The TMED vs IRITR-Cancer Named Binary in Tumour Immunology

Structured Abstract Background Tumour immunology has produced transformative checkpoint inhibitor therapies (anti-PD-1, anti-CTLA-4, anti-PD-L1) that achieve durable responses in 20–30% of patients across solid tumour indications. The dominant explanatory framework — Tumour Mechanism Evades Detection (TMED) — holds that the key determinant of immune surveillance success is what the tumour does: PD-L1 expression, MHC downregulation, Treg recruitment, T-cell exhaustion induction, and neoantigen burden. Despite extensive biomarker development, TMED models cannot reliably predict checkpoint inhibitor response — 70% of patients with approved indications do not respond, and no current biomarker reliably identifies them before treatment. Gap The tradition has a complete account of what tumours do to evade immune detection. It has no structural account of what property of the pre-tumour immune repertoire architecture determines the ceiling of what the immune surveillance system can achieve against a given tumour — a property encoded in the naive and memory TCR and BCR repertoire diversity before any tumour cell has been recognised and operating as a transfer function between neoantigen input and cytotoxic T-cell output. Approach We introduce the IRITR-Cancer framework, which identifies the pre-tumour Tumour-Surveillance Repertoire Diversity Index (TSRDI) — the topological redundancy of functionally non-equivalent T-cell recognition pathways across tumour-associated neoantigen epitope space — as an independently significant determinant of cancer immune surveillance ceiling and checkpoint inhibitor response. We derive the Named Binary TMED vs IRITR-Cancer, identify three structural anomalies TMED cannot resolve, specify a pre-registerable CCS using TCGA immune repertoire (TRUST4) and clinical response data, confirm cross-domain invariance, and derive the IGT Monitoring Principle for cancer immune surveillance. Results IRITR-Cancer resolves three anomalies: the spontaneous regression paradox, the bystander T-cell problem, and the checkpoint inhibitor non-responder paradox. Cross-domain invariance is confirmed with IRITR (acute challenge), immune ageing (Article 18), stroke, TBI, ecology, materials science, and network engineering. The CCS is testable using publicly available TCGA TRUST4 repertoire data and published clinical response datasets at minimal additional cost. Implications If confirmed, IRITR-Cancer restructures immunotherapy patient selection from tumour-side biomarkers (PD-L1, TMB, MSI) to repertoire-architecture-informed stratification; provides a formally derived prediction of checkpoint inhibitor response independent of tumour characteristics; and explains the 70% non-responder problem as a pre-tumour architectural insufficiency, not a tumour escape phenomenon. Weil Protocol: REQUIRED — L3, direct clinical implications for immunotherapy patient selection. Keywords: TMED, IRITR-Cancer, TSRDI, tumour immunoediting, cancer immune surveillance, checkpoint inhibitor, PD-1, PD-L1, TCR repertoire, neoantigen, spontaneous regression, TIL, TCGA TRUST4, ALGUILAS-AI, ARI principle, pre-tumour architecture Method ALGUILAS-AI Dialectical Engine