Tumor cell-intrinsic circular RNA circFNDC3B attenuates CD8+ T cells infiltration in non-small cell lung cancer

Abstract

Tumor-infiltrating CD8+ T cells are critical for anti-tumor immunity and positively associated with patient survival. However, the mechanisms governing CD8+ T cell infiltration remain incompletely elucidated, particularly those involving circular RNAs (circRNAs). In this study, we characterized circRNA expression profiles in four paired normal and tumor tissues of non-small-cell lung cancer (NSCLC) and identified that circFNDC3B, a circular transcript derived from exons 2 and 3 of the fibronectin type III domain containing 3B (FNDC3B) gene, as significantly upregulated in NSCLC tissues. Mechanistic investigations revealed that circFNDC3B directly binds to transcription factor II-I (TFII-I), forming an RNA-protein complex that competitively disrupts the interaction between TFII-I and STAT1. This sequestration abrogates the transcriptional activation of CXCL10 and CXCL11, two critical chemokines governing CD8+ T cell chemoattraction. Consequently, reduced CXCL10/11 expression significantly impairs CD8+ T cell infiltration into the tumor microenvironment. Consistently, the murine ortholog circFndc3b expression exhibits an inverse correlation with CD8+ T cell infiltration in tumors. Our study uncovers a crucial circRNA-mediated regulatory axis wherein circFNDC3B impedes anti-tumor immunity by suppressing chemokine-dependent CD8+ T cell recruitment, positioning circFNDC3B as a potential therapeutic target to enhance CD8+ T cell-mediated anti-tumor responses in NSCLC.