Exosomal circFXR1 drives immune evasion and tumor progression through dual regulation of PD-L1 and mTOR signaling in gastric cancer.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, largely due to aggressive tumor behavior, immune evasion, and limited responsiveness to immunotherapy. Circular RNAs (circRNAs) have emerged as important regulators of cancer progression; however, the roles of exosomal circRNAs in tumor-immune communication in GC remain poorly understood. Here, circRNA profiling of exosomes derived from GC tissues and matched adjacent normal tissues identified circFXR1 as an upregulated circRNA associated with poor survival and adverse clinicopathological features. Functional analyses using GC cell lines, patient-derived organoid, and multiple mouse models demonstrated that circFXR1 promotes tumor proliferation, migration, and growth both in vitro and in vivo. Mechanistically, circFXR1 interacts with miR-497-5p, thereby upregulating PD-L1 expression, which in turn impairs CD8+ T cell-mediated cytotoxicity. In parallel, circFXR1 activates tumor-intrinsic mTOR signaling in a miR-497-5p-dependent manner, further enhancing malignant phenotypes. Importantly, circFXR1 is enriched in tumor-derived exosomes and transferred to recipient tumor cells and CD8+ T cells, resulting in increased PD-L1 expression, impaired T cell effector function, and enhanced tumor progression. Clinically, circFXR1 expression was elevated in non-responders compared with responders to anti-PD-1 therapy. Consistently, in an NSG xenograft model with adoptive transfer of human CD8+ T cells, circFXR1 overexpression attenuated the therapeutic efficacy of anti-PD-1 treatment. Collectively, these findings identify exosomal circFXR1 as a regulator linking tumor-intrinsic signaling and CD8+ T cell-associated immune evasion in GC. CircFXR1 may be associated with anti-PD-1 treatment response in GC, although further validation in molecularly stratified, multi-center cohorts is required.