Necro-mosaic: a lesion-aware framework for testing programmed cell-death-associated mechanisms in tuberculosis

Tuberculosis (TB) can progress despite substantial systemic immune activation, indicating that protection and immunopathology are shaped not only by the magnitude of host responses but also by their organization within individual lesions. TB granulomas are heterogeneous tissue ecosystems in which cellular composition, necrosis, vascular access, extracellular-matrix remodeling, metabolic stress, and local drug exposure vary across lesions and over time. Spatial and single-cell technologies now enable these features to be investigated at increasing resolution; however, spatial or molecular association alone does not establish mechanism, causality, or therapeutic relevance. Here, we propose the Necro-Mosaic framework as a hypothesis-generating, lesion-aware approach for investigating programmed cell death (PCD)-associated processes in TB. The framework is neither a mutually exclusive taxonomy nor a clinical classification system. It considers three non-exclusive, mechanistically framed axes: F-axis, involving ferroptosis-associated lipid-peroxidation injury and membrane damage; P-axis, involving coordinated inflammatory cell-death activity with PANoptosis-like features; and N-axis, involving neutrophil-associated extracellular activity, including NET-associated structures and effector processes. The anatomical distribution, co-occurrence, temporal sequence, and biological consequences of these axis-associated processes remain empirical questions. A single lesion may therefore exhibit one axis-associated pattern, several overlapping patterns, or no interpretable pattern. We distinguish pathway capacity, pathway engagement, and mechanism-specific execution and specify the measurements and controls required to support each level of inference in situ. The framework also defines evidence as established, emerging, or hypothesis-generating according to the strength, reproducibility, resolution, and causal support of the available data. We propose falsifiable predictions to determine whether F-, P-, or N-axis-associated processes act as drivers, amplifiers, or downstream correlates of destructive lesion evolution. Although lesion-resolved host-directed therapy (HDT) is an important long-term objective, current evidence does not support assigning lesion-level mechanistic profiles from blood alone or using these axes to select clinical treatment. Progress will require prospective longitudinal studies, lesion-anchored multimodal validation, perturbation and rescue experiments, spatial pharmacology, and explicit assessment of antimicrobial-preservation and safety risks. By prioritizing testable mechanisms over fixed spatial categories, Necro-Mosaic provides a structured framework for determining how PCD-associated processes may contribute to TB lesion heterogeneity and for identifying which observations are sufficiently validated to support future translational studies.