HIV-associated immune remodeling in cervical cancer: implications for immunotherapy, biomarkers, and trial design

Women living with HIV experience a disproportionate burden of persistent high-risk human papillomavirus infection and cervical cancer, yet they remain underrepresented in pivotal immunotherapy trials. Consequently, the effects of HIV-associated immune remodeling on the cervical cancer tumor immune microenvironment, biomarker interpretation, and response to immune checkpoint inhibition remain poorly defined. In this Review, we synthesize evidence concerning chronic inflammation, T-cell dysfunction and exhaustion, impaired antigen presentation, myeloid-mediated immunosuppression, and mucosal and microbial disruption in cervical cancer among women living with HIV. Because direct evidence in this population remains limited, we distinguish findings derived from HIV-associated cervical cancer from supporting evidence obtained in other HIV-associated malignancies, HIV-negative cervical cancer, and broader studies of HIV, HPV, and mucosal immunology. We propose a provisional inflamed, exhausted, and mucosally disrupted (IEM) framework to organize these interacting immune processes and generate hypotheses for prospective validation. This framework highlights why conventional biomarkers, including PD-L1 expression and peripheral CD4 T-cell counts, may incompletely capture immunotherapy-relevant immune heterogeneity and supports the evaluation of multidimensional biomarkers. We further discuss how the proposed framework could inform mechanism-matched therapeutic hypotheses and a novel two-dimensional clinical trial stratification model, while explicitly emphasizing that IEM is not yet a validated clinical phenotype or routine treatment-selection tool. Prospective studies incorporating women living with HIV are required to determine whether these immune features predict immunotherapy efficacy or toxicity and to establish more inclusive, biologically informed clinical-trial strategies.