Compartmental Oncogenesis: Access Acquisition, Immune Discrimination, and Niche Amplification in Tumor Progression

Central thesis Disease does not begin when pathological potential is generated, but when that potential obtains sustained compartmental access to the conditions that make it consequential. In cancer, the most distinctive form of that access is the one carried out by the altered clone itself as an agent — not as a passive recipient of an external trigger. Abstract We propose that cancer and autoimmunity are opposite-sign failures of the same tissue and immune discrimination system: in autoimmunity, the false positive predominates (a sustained attack against unaltered self tissue); in oncogenesis, the false negative predominates (sustained tolerance or evasion of an altered self clone). Both are instances of the same evolutionary trade-off between sensitivity and specificity from which the ARA theory (Access–Recognition–Amplification) of compartmental autoimmunity starts, and both share a mechanistic substrate — chronic inflammation, repeated tissue repair, niche remodeling — that makes it productive to treat them with a common grammar without merging them into a single theory. We propose that somatic mutation, although necessary, is rarely sufficient: most healthy adult tissues carry mutant clones in driver genes without this leading to clinical cancer, and what most often decides the outcome is whether that clone obtains sustained Access to a permissive niche. This proposal is organized under a four-term framework — Access, Discrimination, Amplification, and Outcome — with three submodalities of Access: exogenous (a carcinogen or pathogen reaches a susceptible niche, of the same sign as ARA), myeloid-stromal (recruitment to the incipient niche), and a third, distinctive of this document, in which the tumor clone itself acts as an agent that gains access to immune protection, metabolic resources, and exit routes — the reverse direction from ARA, where it is the immune response that gains improper access to a protected compartment. The Discrimination stage recovers the immunoediting model already established in oncology (elimination–equilibrium–escape); the Amplification stage describes the inflammatory, angiogenic, and immunosuppressive loops that stabilize the niche. Four domain-specific causality standards are proposed, analogous to those of ARA, and are applied to a bank of six tumors (colitis-associated colorectal cancer, hepatocellular carcinoma from chronic viral hepatitis, HPV-driven cervical cancer, pancreatic ductal adenocarcinoma — developed as a convergence module of three distinct Access pathways, including the bank's first pure Access-as-agent anchor case —, cutaneous squamous cell carcinoma under sustained iatrogenic immunosuppression, and melanoma under checkpoint blockade), plus two frontier cases — paraneoplastic syndromes and checkpoint-inhibitor autoimmune toxicity — that are deliberately kept outside the classification because they belong, strictly, to the domain of ARA, but are developed here in their full complexity because they are the most direct evidence that both programs describe, in at least one real clinical mechanism, the same system from opposite directions. This document deliberately maintains its structural coupling with ARA, exploits the tension of its frontier cases, and maps its own limitations without filter — with the open, still undeveloped possibility that ARA and Compartmental Oncogenesis converge as two branches of a common framework program.