CXCL12 deficiency promotes colorectal cancer progression and reduces anti-PD-L1 immunotherapy efficacy through MDSC regulation.

INTRODUCTION

Several reversal strategies associated with CXCL12, especially the use of CXCR4 antagonists, have been proposed for colorectal cancer (CRC). These strategies have shown some efficacy in clinical trials, but the mechanisms underlying how CXCL12 deficiency contributes to reduced anti-PD-L1 blockade efficacy, a critical barrier to immunotherapy success, remain unclear, highlighting the need for deeper mechanistic exploration and optimized interventions.

METHODS

In this study, the single-cell transcriptome sequencing analysis, in vitro cell experiments and in vivo animal experiments were integrated to identify CXCL12-related RNA binding proteins (RBPs) with causal links to CRC, define key cell types driving resistance, and validate mechanistic insights.

RESULTS

Twelve CXCL12-related RBPs showed causal relationships with CRC. Machine learning methods and diagnostic analysis identified CPEB3, DDX39B, and SIDT2 as biomarkers of CRC. Monocytes were selected as the key CRC cell type based on their biomarker distribution. Single-cell transcription factor analysis screened out two CRC-related transcription factors: MEIS2 and TCF4. In vitro cell experiments and in vivo animal experiments indicated that CXCL12 silencing promoted the migration and invasion capacities of CRC tumor cells. Notably, CXCL12 overexpression combined with PD-L1 antibodies showed the lowest cell viability and invasion capacity, indicating that CXCL12 enhances rather than inhibits anti-PD-L1 therapeutic efficacy Moreover, CXCL12 was negatively correlated with the proportion and number of myeloid-derived suppressor cells.

DISCUSSION: Our identification of CPEB3, DDX39B, and SIDT2 as CRC revealed that CXCL12-related CRC biomarkers, combined with mechanistic evidence linking CXCL12 to MDSC regulation and anti-PD-L1 resistance, provides a novel framework for understanding immunotherapy failure in CRC. These findings might aid in establishing clinical CRC treatment strategies guiding the development of CXCL12-targeted combination strategies to overcome anti-PD-L1 resistance and improve CRC immunotherapy outcomes.