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  • Review Article
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Emerging advances and future opportunities in the molecular and therapeutic landscape of anal cancer

Nature Reviews Clinical Oncology volume 22, pages 483–498 (2025)Cite this article

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Abstract

Anal squamous cell carcinoma (ASCC) is a rare malignancy with an increasing incidence. Primary chemoradiotherapy (CRT) is the standard-of-care treatment for patients with localized ASCC. In the metastatic setting, trials testing immune-checkpoint inhibitor monotherapy have demonstrated outcomes similar to those of patients receiving chemotherapy. Conversely, adding the anti-PD-1 antibody retifanlimab to chemotherapy in patients with recurrent or metastatic ASCC has been shown to significantly improve outcomes. Despite considerable efforts to develop personalized therapy, treatment guidance and prognosis remain reliant on baseline clinical characteristics. An improved understanding of the molecular characteristics of ASCC has provided insights into the mechanisms that mediate tumour progression and response to CRT. For example, human papillomavirus (HPV) infection is known to have an aetiological role in most ASCCs and can modulate cellular responses to CRT via several distinct mechanisms. In this Review, we summarize emerging advances in the molecular and therapeutic landscape of ASCC, including the implementation of biomarkers for treatment guidance and translation into new therapeutic approaches, with HPV infection constituting a global determinant of both tumour biology and clinical outcome. We also discuss the rationale for combining immune-checkpoint inhibitors with CRT in patients with HPV+ tumours.

Key points

  • Anal squamous cell carcinoma (ASCC) is associated with human papillomavirus (HPV) infection, with approximately 70–90% of all patients having HPV+ disease.

  • Despite advances in our understanding of the molecular landscape of ASCC, prognosis and treatment decision-making continue to rely on baseline clinical characteristics.

  • HPV infection has a role in the development of most ASCCs, although paradoxically, patients with HPV+ tumours and high viral loads have better responses and outcomes on standard chemoradiotherapy.

  • The immunomodulatory effects of HPV infection provide a rationale for combining chemoradiotherapy with immunotherapies in patients with HPV+ ASCC.

  • Assessments of molecular biomarkers and the development of molecularly targeted therapies in line with that of emerging immunotherapies might further improve the outcomes of patients with ASCC.

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Fig. 1: Schematic representation of biomarkers associated with either positive or negative response and clinical outcome after standard chemoradiotherapy in patients with ASCC.
Fig. 2: Schematic illustration of the virus-driven mechanisms that mediate treatment response and outcomes in patients with HPV-related cancers.
Fig. 3: Prognosis and therapeutic implications according to HPV status and immune contexture in patients with ASCC receiving CRT.

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Acknowledgements

This work of the authors is supported in part by the LOEWE Center Frankfurt Cancer Institute (FCI) funded by the Hessen State Ministry for Higher Education, Research, and the Arts, III L 5-519/03/03.001 (0015) and the German Federal Ministry of Education and Research (BMBF), grant number Verbund Saturn3: 01KD2206G.

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  1. These authors contributed equally: Daniel Martin, Emmanouil Fokas.

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  1. Department of Radiotherapy and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt, Germany

    Franz Rödel, Maximilian Fleischmann, Markus Diefenhardt, Annett Hoffmann, Claus Rödel & Daniel Martin

  2. Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, Germany

    Franz Rödel, Maximilian Fleischmann, Markus Diefenhardt, Claus Rödel, Daniel Martin & Emmanouil Fokas

  3. German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany

    Franz Rödel, Maximilian Fleischmann, Markus Diefenhardt, Claus Rödel, Daniel Martin & Emmanouil Fokas

  4. Department of Radiation Oncology, Cyberknife and Radiotherapy, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany

    Hendrik Dapper & Emmanouil Fokas

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F.R. and E.F. researched data for the manuscript and made a significant contribution to discussions of content. F.R., C.R. and E.F. wrote the manuscript. All authors edited and reviewed the manuscript prior to submission.

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Rödel, F., Fleischmann, M., Diefenhardt, M. et al. Emerging advances and future opportunities in the molecular and therapeutic landscape of anal cancer. Nat Rev Clin Oncol 22, 483–498 (2025). https://doi.org/10.1038/s41571-025-01025-x

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