Overcoming resistance to immunotherapy in advanced cutaneous squamous cell carcinoma

© 2021 by the authors. Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans, and is now responsible for as many deaths as melanoma. Immunotherapy has changed the therapeutic landscape of advanced CSCC after the FDA approval of anti-PD1 molecules for the treatment of locally advanced and metastatic CSCC. However, roughly 50% of patients will not respond to this systemic treatment and even those who do respond can develop resistance over time. The etiologies of primary and secondary resistance to immunotherapy involve changes in the neoplastic cells and the tumor microenvironment. Indirect modulation of immune system activation with new therapies, such as vaccines, oncolytic viruses, and new immunotherapeutic agents, and direct modulation of tumor immunogenicity using other systemic treatments or radiotherapy are now under evaluation in combined regimens. The identification of predictors of response is an important area of research. In this review, we focus on the features associated with the response to immunotherapy, and the evaluation of combination treatments and new molecules, a more thorough knowledge of which is likely to improve the survival of patients with advanced CSCC. Javier Cañueto is partially supported by the grants GRS2139/A/20 (Gerencia Regional de Salud de Castilla y León), by the PI18/00587 and PI21/01207 (Instituto de Salud Carlos III, cofinanciado con fondos FEDER) and by the “Programa de Intensificación” of the ISCIII, grant number INT20/00074. Sponsors and funders did not influence the design and conduct of the study, the collection, management, analysis, and interpretation of the data, the preparation, review, or approval of the manuscript, or the decision to submit the manuscript for publication.