Therapy-Associated Myeloid Niches as Spatial Drivers of Cancer Treatment Resistance and Targets for Mechanism-Matched Intervention.

Abstract

Tumor drug resistance is still the core obstacle limiting the long-term benefit of modern anticancer therapy, especially in the context of treatment tolerance, persistence of minimal residual disease (MRD) and recurrence after treatment. Increasing evidence has shown that therapy-associated myeloid niches can involve cell recruitment, enrichment of pre-existing populations, or state reprogramming, together with local relationships among myeloid cells, tumor cells, stroma, vessels, and other immune cells. These niches can support residual tumor-cell survival, immune escape, local regrowth, and distant dissemination through overlapping mechanisms linking fibrotic exclusion and perivascular organization with hypoxic metabolic suppression and myeloid replenishment. The formation of neutrophil extracellular traps, failure of antigen uptake and presentation, impaired T-cell priming, and phagocytic escape can further sustain treatment tolerance. Focusing on the myeloid cell state and common molecular circuits, this article presents an evidence assessment framework that interprets spatial and clinical associations alongside functional and pharmacologic findings without assigning hierarchical ranks. It summarizes lessons from clinical failure, considering potentially limited target contributions, compensatory pathways, inadequate exposure, and toxicity, while distinguishing drug exposure and local pharmacodynamic changes from clinical benefit. Candidate biomarkers, intervention windows, and selective delivery approaches require validation to guide mechanism-matched combinations. In the future, longitudinal tissue analyses, functional validation, and prospective studies should test whether these combinations provide durable benefit with acceptable safety in defined patient populations and treatment settings.