Theoretical connotation of synergistic enhancement between the therapy of supplementing qi, promoting blood circulation, and detoxication and immune checkpoint inhibitors from the perspective of the three-level pathogenesis of "vessel flaccidity-vessel impediment-vessel damage"

Although immune checkpoint inhibitors (ICIs) can provide certain therapeutic effects in clinical applications, their clinical benefits are hindered by the characteristics of "cold tumors." Tumor vascular abnormalization is the core bottleneck issue causing this dilemma. Achieving vascular normalization can transform "cold tumors" into "hot tumors," which is key to enhancing the efficacy of ICIs. The Inner Canon of Yellow Emperor delineates vascular disorders through the concepts of vessel flaccidity and impediment: vessel flaccidity denotes malnutrition and the failure of vessel body containment; vessel obstruction signifies coagulates and fails to flow; when impediment aggregates in vessels, it leads to visceral damage and death. These constitute a three-stage evolutionary model of vascular pathology: vessel flaccidity→vessel impediment→vessel damage (vessel impairment). Taking this as the theoretical framework, this paper elucidates the pathogenesis of abnormal tumor vasculature: deficiency initiates vessel flaccidity, qi deficiency fails to nourish endothelial cells, resulting in basement membrane discontinuity; stasis manifests as vessel impediment, blood stasis obstructs collaterals, causing pericyte detachment and interstitial hypertension; toxin culminates in vessel depletion, toxic damage destroys vessel integrity, inducing vasculogenic mimicry and endothelial apoptosis. These three stages progress causally, ultimately leading to "vessel exhaustion and collateral blockage". Accordingly, we propose a stratified intervention strategy of supplementing qi, promoting blood circulation, and detoxication. Supplementing qi to restore vessels counteracts vessel flaccidity by repairing endothelial energy metabolism; promoting blood circulation to unblock vessels relieves vessel impediment by recruiting pericytes and reducing interstitial pressure; detoxication to protect vessels interrupts vessel depletion by inhibiting vasculogenic mimicry and blocking endothelial apoptosis. The synergy of these three approaches restores the containing function of vessel bodies, the patency of vessel pathways, and the regularity of vessel morphology, the essence of tumor vascular normalization in traditional Chinese medicine, and the biological connotation of vessel repair through which supplementing qi, promoting blood circulation, and detoxication synergize with ICIs. This paper reconstructs the pathogenic system of abnormal tumor vasculature from the vessel flaccidity→vessel impediment→vessel damage perspective, providing a coherent theoretical paradigm for traditional Chinese medicine research on tumor vascular normalization.