Spatially-resolved pharmaco-ecology of immunotherapy resistance in lung adenocarcinoma: Single-cell and spatial transcriptomics for mechanism-matched combination therapies

Abstract

Highlights • Immunotherapy resistance in lung adenocarcinoma arises from dynamic interplay among malignant cell plasticity, immune-stromal remodeling, and spatially organized niches.• Single-cell and spatial transcriptomics define five resistance-associated niches: T-cell inflamed with adaptive suppression, immune-excluded stromal boundaries, myeloid-rich hypoxic-metabolic zones, antigen-presentation-low residual foci, and TLS-associated organized areas.• Malignant epithelial cells initiate resistance through altered antigen presentation, IFN/JAK-STAT signaling, partial EMT, and hypoxic-metabolic adaptation, which collectively reshape the microenvironment.• Biomarker strategies should move beyond single markers (e.g., PD-L1, CD8 density) toward composite spatial-ecological signatures that reflect tissue architecture and functional barriers.• Future clinical translation requires protein validation, functional perturbation, multi-region sampling, and prospective trials to convert spatial ecological insights into mechanism-matched combination therapies.