Anti-TIGIT therapies: a review of preclinical and clinical efficacy and mechanisms.

TIGIT (T cell immunoreceptor with Ig and ITIM domains) has garnered interest as a next-generation anti-cancer immunotherapy target, yet its development has been marred by recent clinical failures. This review explores clinical and preclinical studies on TIGIT, examining antibody therapies, co-targeting with other checkpoint inhibitors, mechanistic signaling models, and the role of the Fc region. Here, we discuss how preclinical studies have found antitumor effects from anti-TIGIT antibodies, in particular when using the Fc competent mIgG2 scaffold in combination with anti-PD-1 in smaller-sized tumors. Yet, human monotherapy trials with IgG1 anti-TIGIT have disappointed. We investigate the extent to which combining anti-TIGIT with other treatments (primarily anti-PD-1) improves effectiveness, showing a clear benefit to co-targeting TIGIT, especially in patients positive for PD-L1 expression. We also discuss the Fc region, which has been thought to enhance success through mechanisms like myeloid cell activation, DC modification, and/or Treg depletion, but also risks targeting exhausted T cells for destruction, rather than activating them. The current evidence supports that TIGIT remains an interesting target, especially in Fc silent format, but expectations should be tempered, and research should focus on TIGIT blockade in combination with PD-1 blockade and how to best apply this combination.