Biological mechanisms and clinical implications of HPV-associated and HPV-independent lower anogenital tract malignancies

Cancers of the lower anogenital tract—including the uterine cervix, vagina, vulva, penis, and anal/perianal region—are a heterogenous group unified by shared pathological, etiological, and immunological features. Most of these tumors are squamous cell carcinomas, frequently linked to human papillomavirus (HPV) infection, though a significant subset develop independently of the virus, these latter tumors often showing poorer prognosis. Deciphering the roles of viral-driven mechanisms—such as immune evasion, epithelial barrier disruption and pro-tumoral signaling activation—and intrinsic genomic or epigenetic alterations (e.g., TP53 mutations) remains a central challenge in this field. Existing studies highlight a persistent ambiguity: Which pathways are induced by viral infection versus tissue- or genome-intrinsic factors, and to what extent do these mechanisms overlap or diverge across anatomical subsites? While HPV-associated cancers often display immunologically “hot” microenvironments and show better therapeutic responses, the composition, immunoreactivity, and therapeutic vulnerabilities of HPV-independent tumors require deeper exploration.Recent research underscores the tumor microenvironment (TME) as a pivotal determinant of oncogenesis, immune infiltration, and therapeutic responsiveness in these malignancies. In HPV-driven cancers, viral antigens orchestrate adaptive immune activation, which enhances susceptibility to immunotherapies such as immune checkpoint blockade (ICB) and therapeutic vaccines. Conversely, the limited efficacy of immunotherapies in HPV-independent cancers points toward context-dependent immune landscapes and ongoing immunoregulatory processes yet to be unraveled. Additionally, early phase and translational clinical trials targeting novel immune axes and combinatorial approaches provide opportunities for precision medicine. This growing evidence emphasize the urgent need for integrative studies linking immune cell function, mutational landscapes, and biomarker development to clinical endpoints across both HPV-associated and HPV-independent lower anogenital tract cancers.This Research Topic aims to bridge basic mechanistic and clinical insights surrounding the tumor microenvironment, immune dynamics, and therapeutic response in cancers of the lower anogenital tract. We seek to clarify the contributions of viral and non-viral oncogenic pathways to TME composition, delineate tissue-specific immune variation, identify immunological biomarkers for prognosis and patient stratification, and catalyze the development and translation of novel, site-tailored immunotherapies. By fostering multidisciplinary collaboration, we aspire to advance personalized immuno-oncology in this diverse group of malignancies and improve outcomes for affected patients.Focusing on the pathobiology and clinical management of lower anogenital tract cancers, this topic restricts itself to mechanistic, translational, and clinical research concerning TME composition, immune regulation, and therapeutic innovation in both HPV-associated and HPV-independent settings. We welcome submissions of original research, reviews, perspectives, and clinical trials on—but not limited to—the following themes:• Interactions between HPV-driven mechanisms and intrinsic tumor (genetic, epigenetic, immunological) pathways• Cellular and immune landscape mapping using digital pathology, single-cell, and spatial analyses• Mechanistic studies on immune modulation, functional states, and “hot” versus “cold” TME configurations• Tissue-specific variations in oncogenic pathways and implications for site-tailored therapies• Biomarker discovery and patient stratification for personalized immunotherapy• Development and clinical assessment of emerging immunotherapies, including ICB, vaccines, and ADCs• TME-targeted interventions in HPV-independent tumors, including macrophage/stromal modulation and treatment integration• Role of neoantigens in antitumor immunity and targeted immunotherapeutics• Early-phase and translational trials evaluating novel clinical strategies and immune correlatesThis Research Topic accepts submissions in the following formats: Brief Research Report, Case Report, Classification, Clinical Trial, Editorial, FAIR² Data, General Commentary, Hypothesis and Theory, Methods, Mini Review, Opinion, Original Research, Perspective, Review, Study Protocol, Systematic Review, and Technology and Code. All published articles will undergo rigorous external peer review and may be subject to publication fees. Topic editors: Robert Albero, Natalia Rakislova, Jaume Ordi Source: https://www.frontiersin.org/research-topics/77213/biological-mechanisms-and-clinical-implications-of-hpv-associated-and-hpv-independent-lower-anogenital-tract-malignancies