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