Emerging IO checkpoints in gastrointestinal oncology

Abstract

Recent progress in immunotherapy has significantly altered the therapeutic approach for gastrointestinal cancers, which are historically challenging due to their intricate pathologies and unfavorable outcomes. This review emphasizes the growing importance of immune checkpoints like TIGIT, VISTA, GITR, STING, and TIM-3 in the treatment of gastrointestinal oncology. These checkpoints are crucial elements within the tumor microenvironment, presenting new therapeutic possibilities. Studies show that TIGIT and GITR regulate the functions of T cells and NK cells, while the VISTA and STING pathways boost the body's anti-tumor responses. TIM-3 is linked with T cell fatigue, highlighting its potential as a target to counteract immune evasion mechanisms. Integrating these immune checkpoints with traditional treatments could result in more customized and effective therapeutic approaches. This detailed review seeks to explore the changing field of immune checkpoint research, offering insights from molecular biology to clinical practice, and envisioning a future where advanced treatment methods greatly enhance patient outcomes in GI cancers.

Keywords: GITR; STING; TIGIT; TIM-3; VISTA; cancer immunotherapy; gastrointestinal oncology; immune checkpoints.

Figure 1

Overview of immune checkpoint interactions and therapeutic targets in immunotherapy. (A) TIGIT Pathway: TIGIT competes with CD226 for binding to CD155 on dendritic cells, leading to immune suppression. Anti-TIGIT antibodies block this inhibitory interaction, enhancing T-cell activation by allowing CD226 to bind CD155, thereby boosting anti-tumor immunity. (B) VISTA Pathway: VISTA interacts with VSIG-3 and B7 family members to suppress T-cell responses. VISTA binding to PSGL-1 is significantly enhanced under acidic conditions (pH < 6.5), as found in the tumor microenvironment. Anti-VISTA antibodies disrupt this suppression, restoring T-cell function. Combining anti-VISTA with other checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4) can further enhance T-cell activation and reduce immune evasion by tumors. (C) GITR Pathway: GITR activation by agonistic antibodies or GITRL enhances T-cell cytokine production and immune response. GITR activation also depletes regulatory T cells (Tregs), which suppress immunity. Targeting GITR with bispecific antibodies like anti-PD-1-GITR-L aims to activate effector T cells and reduce Treg-mediated suppression, promoting tumor rejection. (D) TIM-3 Pathway: TIM-3 interacts with galectin-9, CEACAM-1, PtdSer, and HMGB1, contributing to T-cell exhaustion. Anti-TIM-3 antibodies block these inhibitory signals, reinvigorating T-cell function and promoting anti-tumor immunity. TIM-3 blockade is particularly effective when combined with PD-1/PD-L1 inhibitors to overcome multiple layers of immune suppression. Dashed arrows indicate reported cross-regulatory loops (e.g., TIGIT–PD-1 co-inhibition). The figure illustrates the dynamic complexity of immune checkpoint pathways, highlighting potential therapeutic strategies in cancer immunotherapy.

Figure 2

STING pathway activation with agonist delivery strategies. This schematic illustrates activation of the cGAS–STING axis in dendritic cells by (1) tumor-derived cytosolic dsDNA via cGAS conversion to 2′3′-cGAMP and (2) synthetic STING agonists delivered intratumorally, in polymeric nanoparticles, or in liposomal vesicles. Agonist binding induces STING translocation to the Golgi, recruitment of TBK1 and IKK, phosphorylation of IRF3, and NF-κB activation. The resulting type I interferon and pro-inflammatory cytokine production drive DC maturation and CD8⁺ T-cell priming. Clinical translation remains challenging due to inefficient agonist delivery and systemic toxicity.

Figure 3

Interactions of immune checkpoints in the tumor microenvironment. A synthetic STING agonist (blue syringe) binds to the STING adaptor on immature dendritic cells (DCs), triggering production of type I interferons (IFN-β) that activate both DCs and CD8⁺ T cells (brown arrows). Mature DCs present tumor antigens and co-stimulatory signals to CD8⁺ T cells (green arrow), priming cytotoxic responses. Tumor-expressed PD-L1 engages PD-1 on CD8⁺ T cells (red T-bar), dampening TCR signaling. Galectin-9 (GAL-9) and CEACAM-1 on tumor cells bind TIM-3 on CD8⁺ T cells (red T-bars), driving exhaustion. Tumor ligands CD155 and CD112 engage TIGIT on NK cells (red T-bar), inhibiting cytotoxicity, which can be blocked by anti-TIGIT antibody. VSIG-3 and PSGL-1 on tumor cells interact with VISTA on Tregs and DCs (red T-bars), enforcing local immunosuppression, while VISTA blockade (green arrow) restores immune activation. M1 macrophage–expressed GITRL binds GITR on Tregs (green arrow), reinforcing suppression, but a GITR agonist antibody can convert this into co-stimulation on effector T cells. Therapeutic antibodies (anti-PD-1, anti-TIM-3, anti-VISTA, anti-PSGL-1) intercept their respective inhibitory axes to reinvigorate DC, T cell, and NK cell functions.