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

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. Anal squamous cell carcinoma (ASCC) is a rare malignancy, albeit with an increasing prevalence in most economically developed countries. Despite considerable advances in our understanding of the biology of ASCC, chemoradiotherapy (CRT) remains the standard-of-care therapy for most patients, albeit with promising data emerging on the role of CRT plus immune-checkpoint inhibitors in the metastatic setting. In this Review, the authors describe the biology of ASCC and relate this to the various attempts to improve outcomes via the development of more effective systemic therapies and/or combinations.