Exploiting E3 ubiquitin ligases to reeducate the tumor microenvironment for cancer therapy

Abstract

Tumor development relies on a complex and aberrant tissue environment in which cancer cells receive the necessary nutrients for growth, survive through immune escape, and acquire mesenchymal properties that mediate invasion and metastasis. Stromal cells and soluble mediators in the tumor microenvironment (TME) exhibit characteristic anti-inflammatory and protumorigenic activities. Ubiquitination, which is an essential and reversible posttranscriptional modification, plays a vital role in modulating the stability, activity and localization of modified proteins through an enzymatic cascade. This review was motivated by accumulating evidence that a series of E3 ligases and deubiquitinases (DUBs) finely target multiple signaling pathways, transcription factors and key enzymes to govern the functions of almost all components of the TME. In this review, we systematically summarize the key substrate proteins involved in the formation of the TME and the E3 ligases and DUBs that recognize these proteins. In addition, several promising techniques for targeted protein degradation by hijacking the intracellular E3 ubiquitin-ligase machinery are introduced.

Targeting the Interplay of Independent Cellular Pathways and Immunity: A Challenge in Cancer Immunotherapy

“…PROTACs have been described to enhance anticancer immunotherapy by regulating specific proteins, including IDO1, PD-L1, SHP2, HDAC6, HPK1, BCL-xL, BET, NAMPT, and COX-1/2. While the specific role of ubiquitination signaling in the immune defense is still unclear and the immunotherapies targeting ubiquitination are not fully understood, the interplay of the ubiquitin system and TME deserves more investigations in the future [12].…”

“…Although only a few E3 ligases have been used in PROTACs technology, they have several advantages, including good solubility and cell permeability, and are therefore promising for the future. While the specific role of ubiquitin signaling in the immune system is still unclear and the immunotherapies targeting ubiquitination are not fully understood, the interplay of the ubiquitin system and TME deserves more investigations in the future [12]. Ubiquitin signaling is involved in several aspects of the tumor microenvironment (TME), and its dysregulation may contribute to tumor progression.…”

“…Ubiquitination governs PD-1/PD-L1 expression in tumors, thus resulting in an associated clinical response to anti-PD-1/PD-L1 therapy in cancer patients. Targeting ubiquitination could be a potential strategy to potentiate immunotherapeutic effects in cancer patients [11,12].…”

Phase separation-mediated biomolecular condensates and their relationship to tumor

“…Activated ubiquitin is then transferred to the cysteine active site of E2 and binds to it. Finally, E3 ubiquitin ligases facilitate the binding of ubiquitin to the lysine residues of the target protein, resulting in protein ubiquitination [ 150 ]. Among the E3 ubiquitin ligase families, the Cullin-Ring E3 ubiquitin ligase (CRL3) stands out as the largest in the body, forming a multi-protein complex.…”

E3 ligase TRIM28 promotes anti-PD-1 resistance in non-small cell lung cancer by enhancing the recruitment of myeloid-derived suppressor cells

“…A growing body of research has identified several E3 ligases as critical regulators of tumor immune responses [ 12 ]. Certain drugs targeting E3 ubiquitin ligases have demonstrated promising effects in preclinical and clinical antitumor treatments [ 13 ]. However, the specific roles of E3 ligases in cancer cells, particularly in the context of drug resistance in cancer immunotherapy, remain inadequately understood.…”