Predictive Value of CCL3 Expression Levels for Therapeutic Response in Patients with Locally Advanced Cervical Cancer

Abstract

Rationale: Locally advanced cervical cancer (LACC) exhibits profound therapeutic heterogeneity, with therapy resistance heavily influenced by the immunosuppressive tumor microenvironment. The myeloid compartment, particularly tumor-associated macrophages (TAMs), serves as a key mediator of this therapeutic resistance, yet the precise molecular hubs for predicting neoadjuvant chemotherapy (NACT) sensitivity remain insufficiently characterized. Objectives: This study aims to decipher the myeloid-driven mechanisms of chemoresistance and validate the clinical utility of the chemokine CCL3 as a predictive and prognostic biomarker in LACC patients to optimize personalized treatment strategies. Methods: We integrated single-cell transcriptomics (GSE236738) from six LACC patients with high-dimensional Weighted Gene Co-expression Network Analysis (hdWGCNA) to identify macrophage-specific functional modules and hub genes. Subsequent retrospective clinical validation was conducted via immunohistochemistry (IHC) on pre-treatment primary tumor biopsies from a cohort of 33 LACC patients receiving NACT, correlating CCL3 protein expression with RECIST outcomes and survival trajectories. Measurements and Main Results: Single-cell analysis revealed a substantial expansion of macrophages, accounting for approximately 35% of the immune infiltrate. hdWGCNA pinpointed the chemokine CCL3 as the central hub gene driving this macrophage functional polarization. In the clinical cohort, elevated CCL3 expression was significantly linked to diminished chemosensitivity and a poor pathological response, characterized by higher median Tumor regression rate (based on RECIST 1.1)s (0.31 vs. 0.57; P = 0.001). Furthermore, univariate Cox regression and Kaplan-Meier analyses confirmed that high CCL3 expression shows potential as a reliable prognostic factor for both reduced progression-free survival (HR = 1.190; P = 0.004) and overall survival (HR = 1.278; P < 0.001). Conclusions: CCL3 is a pivotal orchestrator of macrophage-mediated immune exclusion and chemoresistance in LACC. Assessing CCL3 expression levels provides a promising predictive tool for NACT sensitivity and a vital prognostic indicator, offering actionable insights for developing targeted immunotherapies and advancing precision oncology for LACC management.