Authors
Lung, B. C.-c., Leung, A. K.-k., Liu, S., Wong, C. W.-Y., Lai, T. H., Wong, I. Y.-h., Lung, C. C. H., Lo, A. W.-i., Kam, N.-W., Ko, J. M.-Y., Dai, W., Kwong, D. L.-w., Law, S., Scodeller, P., Lung, M., Yu, V. Z.
Abstract
Responses to macrophage-directed therapy can be transient because tumors preserve myeloid support through complementary persistence and replenishment. In esophageal squamous cell carcinoma (ESCC), CSF1R inhibition reduced established tumor-associated macrophages but was followed by expansion of Ly6C/CCR2-positive monocytic and Ly6G-positive granulocytic populations. Low-dose decitabine preferentially restricted recruited populations while sparing a LYVE1-associated macrophage state, exposing reciprocal pharmacologic blind spots. Combined treatment suppressed both arms and produced sustained control across patient-derived organoid xenograft, orthotopic, and immunocompetent models. Neutrophil depletion reproduced initial regression but not sustained control, indicating that the recruited escape arm extended beyond Ly6G-positive granulocytes. Single-cell profiling mapped these vulnerabilities onto a treatment-resolved myeloid architecture comprising a C1qa-positive TAM continuum, a C1qa-negative Ccr2/Ly6c2-high inflammatory monocytic-like compartment, and a LYVE1/MRC1-positive tissue-supportive macrophage state. Human ESCC contained corresponding macrophage programs and an adverse-outcome-associated LYVE1-rich niche. These findings identify state-aware coverage of complementary myeloid vulnerabilities as a strategy to overcome escape from macrophage-directed therapy.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 29 Aug 2026.
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