Astragaloside IV and tumor microenvironmental barriers: immune mechanisms, evidence hierarchy, and implications for checkpoint blockade

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, primary and acquired resistance remain prevalent in solid tumors. Challenges such as poor T-cell infiltration, spatial T-cell exclusion, and T-cell dysfunction present distinct yet interrelated obstacles that may hinder checkpoint blockade effectiveness. Astragaloside IV (AS-IV) exhibits anti-inflammatory, antioxidant, endothelial-protective, antifibrotic, and metabolism-modulating properties relevant to the tumor microenvironment (TME). Rather than functioning merely as a conventional systemic immune stimulant, AS-IV may be more effectively viewed as a modulator of local structural, cellular, and metabolic conditions that influence checkpoint-blockade responsiveness. This Review critically examines preclinical evidence linking AS-IV to tumor immune regulation and ICI responses. A total of twenty primary studies comprise the core evidence base: six studies evaluating direct combinations of free AS-IV with checkpoint blockade, nine representative tumor-specific mechanistic investigations without direct ICI testing, and five studies on ICI combinations utilizing AS-IV-containing formulations or delivery systems. Tumor-specific findings connect AS-IV with the PPP1R14B/CX3CL1/CD8 + T-cell and MCT1/lactate pathways, macrophage-associated states, cancer-associated fibroblast activity, and context-dependent PD-L1 regulation. Direct combinations of free AS-IV and ICIs have demonstrated superior antitumor activity compared to respective monotherapies in several models, though formal pharmacological synergy remains unproven. Most models lacked adequate characterization of pretreatment spatial immune phenotypes, and increases in CD8 + T-cell measures or combination benefits post-treatment do not confirm “cold-to-hot” conversion. Proposed effects on tumor vascular normalization, ECM remodeling, perfusion, and hypoxia primarily rely on indirect or cross-contextual evidence. Thus, AS-IV should be viewed as a potential TME-modulating adjunct to ICIs rather than a well-established component of ICI combination therapy. Further research is necessary to delineate tumor-specific causal mechanisms, pharmacologically relevant exposure levels, responsive TME phenotypes, optimal treatment schedules, and combination safety.