Simple SummaryLaryngeal cancer is a relatively common neoplasm of head and neck, whose management hinges on a combination of treatments such as surgery, radiotherapy and chemotherapy. Tumor recurrences may present important differences from the primary tumor that largely depend on previous treatments. the immune system plays a crucial role in the natural course of the disease, owing the capability to influence its behavior through a complex interaction of mechanisms. For this reason, the use of immunotherapy in addition to standard therapies is increasingly gaining importance nowadays and the selection of patients who can benefit the most from this treatment can help optimizing its success. However, conventional treatments can induce relevant changes in the host immune response, thus affecting tumor progression and patient outcome. This fact should be taken into account when planning immune-based treatments like immune checkpoint inhibitors. In this article, we review the histologic and molecular treatment-induced changes that may affect the diagnosis of recurrent laryngeal cancer, the assessment of predictive markers, and the response to treatment with immune checkpoint inhibitors.AbstractRecurrent laryngeal carcinoma presents differences from the primary tumor that largely depend on the treatment. In this article, we review the histologic and molecular treatment-induced changes that may affect the diagnosis of recurrent laryngeal carcinoma, the assessment of predictive markers, and the response to treatment with immune checkpoint inhibitors. Radiotherapy induces profound modifications that are strictly related to necrosis of different tissue components, fibrosis, and damage of the tumor vessels. Postradiotherapy recurrent/persistent laryngeal squamous cell carcinoma typically presents a discohesive growth pattern within a fibrotic background associated with significant changes of the tumor immune microenvironment, with both important immunosuppressive and immunostimulatory effects. Overall, the increase of immunoregulatory cells and immune checkpoints such as CTLA-4, TIM-3, PD-1, and PD-L1 induced by radiotherapy and chemotherapy strongly supports the use of immune checkpoint inhibitors in recurrent/persistent laryngeal carcinoma. Future studies aiming to identify predictive factors of the response to immune checkpoint inhibitors should consider such treatment-induced modifications.