Pharmacological Disruption of Druggable Immunosuppressive Circuits to Re-Sensitize Tumors to Checkpoint Blockade

Immune checkpoint blockade (ICB) has transformed cancer therapy, yet durable clinical benefit remains limited by primary and acquired resistance. Resistance is increasingly sustained by localized immunosuppressive niches formed by suppressive immune cell populations, stromal remodeling, metabolic constraints, and altered tissue architecture. Although these resistance mechanisms have been extensively characterized, their translation into defined pharmacological interventions with measurable target engagement remains insufficient.This Research Topic focuses on the pharmacology of agents that disrupt discrete, druggable immunosuppressive circuits to restore checkpoint sensitivity and improve response durability. Emphasis will be placed on mechanism of action, target engagement, dose–exposure–response relationships, PK/PD, rational combination scheduling with ICB, and biomarker-defined niche signatures that support patient stratification and translational development.We welcome Original Research, Methods, Reviews, and Perspectives that connect mechanistic pharmacology with translational or clinical readiness. Topics of interest include, but are not limited to:• Agents targeting defined suppressive immune cell circuits, including TAMs, MDSCs, Tregs, and tolerogenic dendritic cells, with evidence of target engagement, selectivity, and functional immune restoration.• Metabolic-circuit drugs that relieve local immune suppression, including agents targeting adenosine/CD39–CD73 signaling, hypoxia, lipid metabolism, or nutrient competition.• Stromal- and CAF-directed agents that reverse immune-exclusion phenotypes and improve immune cell access to tumors.• Mechanism-driven combinations with immune checkpoint blockade, including dose optimization, sequencing, scheduling, and resistance-prevention strategies.• Biomarker- and spatially guided identification of resistance-associated suppressive programs used to nominate drug targets, stratify patients, or evaluate pharmacological remodeling.• PK/PD and translational pharmacology studies bridging preclinical niche remodeling to early-phase clinical implementation.Submissions must center on anti-cancer drugs and their pharmacological mechanisms. Descriptive resistance-mechanism studies, prognosis-only studies, toxicity-only studies, and manuscripts focused primarily on natural products or traditional medicine are outside the scope of this Research Topic. Topic editors: Dawei Chen, Kang Wang, Wenjing Zhou, Yushen Wu Source: https://www.frontiersin.org/research-topics/82986/pharmacological-disruption-of-druggable-immunosuppressive-circuits-to-re-sensitize-tumors-to-checkpoint-blockade