Promising New Anti-TIGIT Agents: Stealthy Allies in Cancer Immunotherapy

Abstract

TIGIT (T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain), Vstm3, and VSIG9, are newly recognized immunological checkpoints. They are prominently expressed on CD4+ and CD8+ T cells, tumor-infiltrating lymphocytes (TILs), natural killer (NK) cells, and regulatory T cells (Tregs). The TIGIT (TIGIT) protein is crucial for immune modulation since it diminishes NK cell populations and hinders T cell activity in cancer patients and experimental models. CD155, the principal ligand of TIGIT in humans, has been recognized as a pivotal target for immunotherapy owing to its interaction with TIGIT. CD155 is linked to the efficacy of anti-programmed cell death protein 1 (PD-1) therapy, even without TIGIT expression, underscoring its importance in immune checkpoint suppression. Anti-TIGIT medicines, either independently or in conjunction with anti-PD-1 treatments, have demonstrated potential in augmenting immune responses to malignancies. This review examines the structural and functional characteristics of the TIGIT protein, new developments in anti-TIGIT drugs, and their prospective use in cancer immunotherapy.

Keywords: PD‐1; TIGIT; cancer; immunotherapy; resistance.

FIGURE 1

TIGIT receptors and ligands interaction. Modified from [15].

FIGURE 2

Mechanisms of TIGIT inhibition of T cells. TIGIT displays multiple inhibitory mechanisms in T cells. (a) TIGIT signaling in Tregs increases their immunosuppressive properties. (b) Fap2 protein from the Fusobacterium nucleatum binds TIGIT to trigger inhibitory signals. (c) TIGIT binds CD155 with greater affinity than CD226 or disrupts homodimerization of CD226 to impede CD226‐mediated T cell activation. (d) TIGIT adheres CD155 on APCs to spark IL‐10 production and decrease IL‐12 production, indirectly inhibiting T cells. (e) TIGIT binds CD155 and produces direct inhibitory signals in T cells. Modified from [15]. Re‐use permitted under CC BY‐NC.

FIGURE 3

Factors affecting the expression of TIGIT. Preferably, (A) glucose deprivation, microwave ablation, hypoxic conditions, as well as the presence of CCL23, IL‐10, inhaled IL‐15, and anti‐PD‐1/PD‐L1 therapies would enhance the expression of TIGIT, In contrast, (B) chemotherapy agents, Interferon‐I (IFN‐I), GITR antibodies, and 1α,25‐Dihydroxyvitamin D3 would downregulate its expression, thereby paving towards an immunosuppressive TME. Modified from [15].