ADAM12 in a stromal-checkpoint framework: integrating tumor microenvironment remodeling and therapy resistance in solid tumors.
- 1Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, 150 Haping Road, Harbin, Heilongjiang, 150081, China.
- 2Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.
- 3Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, 150 Haping Road, Harbin, Heilongjiang, 150081, China. [email protected].
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.
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BibTeX
@article{liu2026adam12,
title = {{ADAM12 in a stromal-checkpoint framework: integrating tumor microenvironment remodeling and therapy resistance in solid tumors.}},
author = {Shaochun Liu and Jian Xu and Han Zhang and Yuhan Tang and Xiaoxi Han and Wenjing Xiong and Linlin Fan and Chang Su and Zhiqi Sui and Wenhui Zhao},
journal = {Cell communication and signaling : CCS},
year = {2026},
month = jul,
doi = {10.1186/s12964-026-03103-8},
url = {https://europepmc.org/article/MED/42902290},
note = {CC BY},
}
RIS
TY - JOUR
TI - ADAM12 in a stromal-checkpoint framework: integrating tumor microenvironment remodeling and therapy resistance in solid tumors.
AU - Shaochun Liu
AU - Jian Xu
AU - Han Zhang
AU - Yuhan Tang
AU - Xiaoxi Han
AU - Wenjing Xiong
AU - Linlin Fan
AU - Chang Su
AU - Zhiqi Sui
AU - Wenhui Zhao
PY - 2026
DA - 2026/07/01
JO - Cell communication and signaling : CCS
DO - 10.1186/s12964-026-03103-8
UR - https://europepmc.org/article/MED/42902290
AB - 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.
SN - 1478-811X
ER -