Compartmental Oncogenesis: A Framework of Access, Discrimination, and Amplification in Cancer Development

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), although oncogenic progression can also arise through co-option of recruited host responses rather than simple surveillance failure. 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 formalize the oncogenic branch here as ADA (Access–Discrimination–Amplification), a sister grammar to ARA; Outcome is kept outside both acronyms because it is the phenotype produced by those interacting causal functions rather than a fourth causal operation. 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. ADA retains the four Access submodalities developed in this document: exogenous (a carcinogen or pathogen reaches a susceptible niche, of the same sign as ARA), myeloid-stromal (recruitment to the incipient niche), Access-as-agent (the tumor clone itself gains access to immune protection, metabolic resources, and exit routes), and negative Access (a tissue structurally denies those resources to mutant clones already present within it). Discrimination recovers the immunoediting model already established in oncology (elimination–equilibrium–escape). This version makes explicit a Functional configuration layer between the core operation and downstream Amplification: a persistent or semi-persistent tumor–immune–stromal organization that conditions how subsequent inputs are handled. Immunoediting equilibrium is the clearest canonical ADA candidate for this layer, but the classic T-cell/IFN-γ depletion experiment demonstrates dependence on the Discrimination machinery itself rather than an independent rescue of configuration; four-test closure is therefore not claimed. Co-option is treated as a cross-cutting mode of interference, in which a recruited host effector or response architecture is redirected into tumor support rather than containment; it is not a third Discrimination value or an additional temporal step. Amplification describes the inflammatory, angiogenic, stromal, and immunosuppressive loops that stabilize the niche. Five domain-specific causality standards are proposed, analogous to those of ARA, and are applied to a bank of twelve tumors (colitis-associated colorectal cancer, hepatocellular carcinoma developed as a convergence module of chronic viral hepatitis, alcohol-related injury, and aflatoxin B1 exposure, 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 —, UV-associated cutaneous carcinogenesis represented by cutaneous squamous cell carcinoma under sustained iatrogenic immunosuppression and melanoma under checkpoint blockade, tobacco-associated lung cancer as the bank's first integrated chemical-carcinogen ADA case, alcohol/acetaldehyde-associated esophageal squamous cell carcinoma as the bank's human metabolic-Access anchor, asbestos-associated malignant pleural mesothelioma as the bank's first fibrous particulate Access anchor, obesity-associated endometrial/postmenopausal breast cancer as a self-generated Amplification/niche case, respirable crystalline silica-associated lung cancer as a strong-candidate granular particulate pathway, and central chondrosarcoma as the bank's first negative-Access control), 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, now formalized as the ARA/ADA pairing, exploits the tension of its frontier cases, and maps its own limitations without filter — with the open, still undeveloped possibility that ARA and ADA converge as two branches of a common framework program. A separate experimental modifier case is also developed outside the core tumor bank: in mouse models, a specific lipid-nanoparticle formulation can generate a transient distal pro-metastatic niche through local tissue injury, mtDNA release, neutrophil activation, and NETosis, illustrating that exogenous Access in one compartment can alter tumor outcome in another without being mutagenic or tumor-derived. The exogenous-Access arm is further consolidated by ultraviolet radiation as a physical dual-axis mutagenic/immunomodulatory exposure and by aflatoxin B1 as a metabolically activated hepatocarcinogen that converges with HBV on HCC. Particulate aluminum is retained only as an exploratory frontier modifier: aluminum-containing particulates can activate inflammasome signaling, and aluminum-oxide nanoparticles can indirectly increase malignant traits experimentally, but no human cancer signal sufficient for core-bank classification is claimed.