Divergent immune ecosystems in HPV-associated and HPV-independent lower anogenital tract malignancies

Lower anogenital tract malignancies comprise anatomically adjacent but biologically heterogeneous epithelial cancers of the cervix, vulva, vagina, anal canal and penis. This narrative and conceptual Review used a transparent literature search to examine how human papillomavirus (HPV) etiology intersects with tumor lineage, somatic alterations, antigen-presentation competence, immune-cell state and spatial organization. Evidence quality is heterogeneous: cervical cancer is supported by the largest genomic, single-cell, spatial and randomized-trial literature, whereas vaginal, vulvar and penile cancers remain constrained by small retrospective cohorts and cross-site extrapolation. HPV-associated tumors retain non-self E6/E7 antigens, but viral transcription does not ensure peptide presentation, dendritic-cell priming or epithelial access by functional T cells. HPV-independent tumors lack constitutive viral antigens yet may generate mutation- or differentiation-derived immunity and checkpoint-restrained myeloid-lymphoid niches. We therefore distinguish etiological status from functional immune phenotype and critically appraise three spatial architectures-an inflamed/epithelial-penetrating pattern, a stromally excluded pattern, and an immune-desert pattern-together with an immunosuppressive functional overlay that may occur in any architecture. Clinical evidence is graded separately from mechanistic inference: immune checkpoint blockade has established roles in defined cervical and anal cancer settings, whereas therapeutic vaccines, tumor-infiltrating lymphocytes, T-cell receptor-engineered therapies, myeloid or stromal sensitization and artificial-intelligence-guided selection remain investigational or context dependent. A three-tier biomarker framework is proposed, separating routine clinical assays from extended translational profiling and exploratory single-cell, spatial and artificial-intelligence methods. This framework is hypothesis-generating, not a validated treatment-selection algorithm; assay combinations, thresholds and incremental clinical utility require prospective, multicenter and site-stratified validation.