G3BP1 and SLU7 Jointly Promote Immune Evasion by Downregulating MHC‐I via PI3K/Akt Activation in Bladder Cancer

Abstract

Abstract Immune checkpoint inhibitors (ICIs) show promise as second‐line treatment for advanced bladder cancer (BLCA); however, their responsiveness is limited by the immune evasion mechanisms in tumor cells. This study conduct a Cox regression analysis to screen mRNA‐binding proteins and reveals an association between Ras GTPase‐activating protein‐binding protein 1 (G3BP1) and diminished effectiveness of ICI therapy in patients with advanced BLCA. Subsequent investigation demonstrates that G3BP1 enhances immune evasion in BLCA cells by downregulating major histocompatibility complex class I (MHC‐I) through phosphoinositide 3‐kinase (PI3K)/Akt signaling activation. Mechanistically, G3BP1 interacts with splicing factor synergistic lethal with U5 snRNA 7 (SLU7) to form a complex with poly(A)‐binding protein cytoplasmic 1 and eukaryotic translation initiation factor 4 gamma 1. This complex stabilizes the closed‐loop structure of the mRNAs of class IA PI3Ks and consequently facilitates their translation and stabilization, thereby activating PI3K/Akt signaling to downregulate MHC‐I. Consistently, targeting G3BP1 with epigallocatechin gallate (EGCG) impedes immune evasion and sensitizes BLCA cells to anti‐programmed cell death (PD)‐1 antibodies in mice. Thus, G3BP1 and SLU7 collaboratively contribute to immune evasion in BLCA, indicating that EGCG is a precision therapeutic agent to enhance the effectiveness of anti‐PD‐1 therapy.

Keywords

• bladder cancer
• epigallocatechin gallate
• immune checkpoint inhibitors
• immune evasion
• major histocompatibility complex class I
• Ras GTPase‐activating protein‐binding protein 1