Work

Disrupting Myeloid Persistence and Replenishment Enables Sustained Control of Esophageal Squamous Cell Carcinoma

Year: 2026

Type: preprint

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. Statement of Significance Macrophage-directed therapy can fail when established tumor-associated macrophage states and recruited myeloid populations remain incompletely covered by a single intervention. In ESCC, jointly suppressing complementary persistence and replenishment compartments converted heterogeneous, incomplete responses into sustained control across models, defining a state-aware myeloid coverage principle for biomarker-guided combination therapy.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.08.27.747541