CDK9 Governs Splicing Fidelity as an Active Immune Checkpoint in cGAS-MITA/STING-Silenced Tumours

While global splicing dysregulation has been associated with tumour immunogenicity, it remains unclear whether cancer cells actively maintain splicing fidelity to evade immune surveillance. Here, we show that the kinase CDK9 functions as an innate immune checkpoint by enforcing RNA splicing fidelity, particularly in cancers with silenced cGAS-MITA/STING signaling. Through phosphorylation of specific splicing factors, designated splicing entropy-regulating core factors (SERCFs) such as SRSF2 at Ser212, CDK9 suppresses splicing entropy. Disruption of this regulatory axis not only leads to the accumulation of immunogenic double-stranded RNAs (dsRNAs) that activate RLR–VISA/MAVS-dependent antiviral pathways but also generates public neoantigens (e.g., NeoARAB18), which are experimentally validated as potent activators of human T cells. Consistently, clinical analyses and in vivo experiments demonstrate that CDK9 inhibition reprograms the tumour microenvironment (TME) and enhances responses to immune checkpoint blockade (ICB) therapy in ER+ breast cancer. Furthermore, pan-cancer analysis extends this mechanism to cGAS-MITA/STING-silenced, immunologically cold tumours, revealing that elevated CDK9 expression and suppressed VISA/MAVS signaling jointly constitute a dual mechanism for immune evasion. Our findings go beyond the observation that splicing errors can trigger immune responses by demonstrating how a pharmacologically targetable kinase actively maintains splicing precision as an intrinsic immune checkpoint, thereby protecting the epitranscriptome from self-recognition.