Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Cancer stem cells (CSCs) are crucial drivers of tumor recurrence, immunotherapy resistance, and drug resistance.
• The tumor-associated immune microenvironment (TAIM) significantly influences CSC heterogeneity, plasticity, and evolution.
• CSCs establish an inhibitory TAIM (ITAIM) via stemness-related signaling pathways (SRSs): Notch-NF-κB, Hedgehog, Wnt, and STAT.

Purpose of the Study:

• To review the role of deubiquitinating enzymes (DUBs), particularly Ubiquitin-specific peptidases (USPs), in regulating CSCs and ITAIM.
• To highlight USPs as potential therapeutic targets for reversing immunosuppression and enhancing anti-tumor immunity.

Main Methods:

• Literature review focusing on the involvement of USPs in CSC signaling and ITAIM regulation.
• Analysis of how ubiquitination/deubiquitination processes impact ITAIM and CSC stemness.
• Examination of the functions of USPs in regulating tumor immunogenicity, stem cell factors, SRSs, and inflammatory mediators.

Main Results:

• USPs play critical roles in ITAIM by modulating tumor immunogenicity, activating stemness factors, upregulating SRSs, and influencing inflammatory signaling.
• Dysregulated USP activity can dampen anti-tumor immune responses, contributing to CSC-mediated immune evasion.
• Inhibition of specific USPs shows potential for regulating SRSs and reversing ITAIM.

Conclusions:

• USPs are key regulators of the interplay between CSCs and the immune microenvironment.
• Targeting USPs represents a promising therapeutic strategy to overcome CSC-driven tumor resistance and enhance the efficacy of cancer immunotherapy.
• Further investigation into USP functions in CSCs and ITAIM is warranted for developing novel anti-cancer therapies.