ADAM12 in a stromal-checkpoint framework: integrating tumor microenvironment remodeling and therapy resistance in solid tumors

Abstract The tumor microenvironment (TME) is now understood as an active regulator of therapeutic vulnerability. In this Review, we use an integrative stromal-checkpoint framework, informed by published stromal and fibroblast checkpoint studies, to describe stromal programs that couple extracellular matrix (ECM) remodeling, metabolic stress, vascular dysfunction, and immune exclusion into treatment-resistant tumor ecologies. We focus on a disintegrin and metalloproteinase 12 (ADAM12) because ADAM12-high or ADAM12-positive tumor-stromal states have been linked to collagen-rich desmoplasia, mechanotransduction, hypoxia-associated stress, lactate-associated acidosis, immune-excluded spatial organization, and therapy resistance in solid tumors. Evidence spans fibroblast, mesenchymal stromal-cell, and tumor-cell perturbation studies; mechanistic substrate and signaling analyses; spatial and clinical datasets; and broader tissue-level immune contexts relevant to lymphatic drainage, tumor-draining lymph node (TDLN) priming, tissue-resident immune cells, and ILC2/type 2 immune programs. Across these evidence layers, ADAM12 emerges as an isoform-aware and cell-of-origin-dependent marker, amplifier, and context-dependent candidate target for selected high-barrier tumor states. We discuss how ADAM12-informed biomarkers, spatial barrier profiling, and stromal-priming strategies can support patient stratification and combination-therapy design. Overall, ADAM12-associated biology provides a useful model for examining how stromal resistance may be built, maintained, and therapeutically remodeled in selected tumor contexts.