Ubiquitin-specific proteases and the immune microenvironment in cervical cancer: mechanistic evidence, immunotherapy resistance, and therapeutic perspectives.

Cervical cancer remains a major global health burden, and resistance limits the benefit of immune checkpoint inhibitors (ICIs). Ubiquitin-specific proteases (USPs) regulate protein homeostasis and may connect human papillomavirus-associated oncogenesis with immune evasion. This narrative review evaluates USP-dependent mechanisms relevant to cervical cancer, distinguishing disease-specific findings from evidence in other tumor types and proposed pathways. Cervical cancer studies support USP7-associated immune-checkpoint regulation and USP14-dependent MCT4 stabilization and lactate export, although the immune consequences of the latter remain inferred. Evidence linking USPs to regulatory T-cell function, STING signaling, antigen presentation, and immunosuppressive metabolism derives largely from non-cervical experimental systems. The proposed E6-USP7 and E7-USP1 immune pathways therefore require direct validation. We discuss small-molecule inhibitors, targeted protein degradation and stabilization, combination strategies, and biomarker development. Compensatory USP Reprogramming (CUR) and a proposed USP-based tumor immune microenvironment (USP-TIME) framework are presented as hypotheses for investigating treatment-associated adaptation and the relationship between USP profiles and immune architecture, respectively. Therapeutic development must account for the possibility that USP inhibition also impairs antigen presentation or effector lymphocyte function. Although USP-directed approaches provide a rationale for further investigation, their clinical benefit in cervical cancer remains unproven. Progress requires cell-type-resolved mechanistic studies, immunocompetent models, validated pharmacodynamic assays, and compound-specific safety assessment.