The majority of patients with colorectal cancer (CRC) show only modest responses to anti-programmed cell death protein 1 (PD-1) treatment, and the precise reasons for this limited efficacy are not yet clear. Circular RNAs (circRNAs) are known to exert substantial influence on tumor formation and progression, offering possible utility in early detection and prediction of therapeutic outcomes. Nevertheless, investigations into the contribution of circRNAs to immune evasion in CRC remain scarce. Differential expression analysis of circRNA microarrays identified circPHLPP2. The association between circPHLPP2 levels and various clinicopathological parameters in CRC patients was assessed using RT-qPCR. Functional studies involving MTS assays, colony formation experiments, in vivo subcutaneous tumor models, and multicolor flow cytometry were conducted to clarify the role of circPHLPP2. Downstream molecular pathways were examined through RNA-seq, RT-qPCR, and Western blotting. Protein partners of circPHLPP2 were identified with RNA pull-down assays, RNA immunoprecipitation (RIP), and immunofluorescence staining. Expression of circPHLPP2 is elevated in CRC patients who do not respond adequately to anti-PD-1 therapy. This circRNA strongly drives CRC cell proliferation and accelerates tumor growth in experimental models. Silencing circPhlpp2 improves the antitumor activity of anti-PD-1 agents in vivo. At the mechanistic level, circPHLPP2 binds directly to ILF3, thereby promoting its nuclear accumulation. Nuclear ILF3 then augments IL36γ gene transcription, which in turn decreases the recruitment of NK cells into the tumor and suppresses their secretion of granzyme B and IFN-γ, ultimately supporting tumor advancement. In summary, this study identifies a previously unrecognized pathway by which a circRNA controls immune escape in CRC. circPHLPP2 represents a potential prognostic indicator and a candidate therapeutic target for improving outcomes in CRC patients.
