TRIP13: A promising cancer immunotherapy target

Abstract

The tumor microenvironment (TME) facilitates tumor development through intricate intercellular signaling, thereby supporting tumor growth and suppressing the immune response. Thyroid hormone receptor interactor 13 (TRIP13), an AAA+ ATPase, modulates the conformation of client macromolecules, consequently influencing cellular signaling pathways. TRIP13 has been implicated in processes such as proliferation, invasion, migration, and metastasis during tumor progression. Recent studies have revealed that TRIP13 also plays a role in immune response suppression within the TME. Thus, inhibiting these functions of TRIP13 could potentially enhance immune responses and improve the efficacy of immune checkpoint inhibition. This review summarizes the recent research progress of TRIP13 and discusses the potential of targeting TRIP13 to improve immune-based therapies for patients with cancer.

Keywords: immune responses; immune‐based therapies; thyroid hormone receptor interactor 13; tumor microenvironment.

Figure 1

Schematic of ATP hydrolysis of TRIP13 in mitosis and meiosis. During mitosis, TRIP13 binds to the N terminus of MAD2, in the presence of p31^comet, causing the conversion of C‐MAD2 into O‐MAD2. TRIP13 inhibits the spontaneous conversion of O‐Mad2 into C‐Mad2, preserving a reservoir of soluble O‐Mad2. O‐Mad2 is then attracted to kinetochores during mitosis, contributing to the formation of the mitotic checkpoint complex. During meiosis, TRIP13 facilitates the removal of various HORMAD proteins, resulting in the synthesis of the synaptonemal complex. C‐MAD2, closed MAD2; MAD2, mitotic arrest deficient 2; O‐MAD2, open‐MAD2; PCH2, pontocerebellar hypoplasia type 2; TRIP13, thyroid hormone receptor interactor 13.

Figure 2

Illustration of the mechanism underlying the antitumor effect and immune response of targeting TRIP13. DCZ04145 inhibits the TRIP13‐FGFR4‐STAT3 axis, inactivates NF‐κB and Wnt/β‐catenin signaling, activates antitumor immune response, and reduces tumor progression and metastasis. CTLA‐4, cytotoxic T‐lymphocyte associated protein 4; FGF, fibroblast growth factor; FGFR4, fibroblast growth factor receptor 4; NF‐κB, nuclear factor‐κB; PD‐1, programmed cell death protein 1; PD‐L1, programmed death‐ligand 1; STAT3, signal transducer and activator of transcription 3; TRIP13, thyroid hormone receptor interactor 13.