Background: Radical chemoradiotherapy (CRT) is the standard of care in patients with localized anal squamous cell carcinoma; however, around 30% of patients do not achieve a complete clinical response (CCR) and require savage surgery. Approximately 84% of anal carcinoma is associated with high risk types of human papilloma virus (HPV), primarily HPV 16 that generates high frequencies of tumor-infiltrating lymphocytes and inflammatory responses that have been linked with upregulation of PD-L1 (up to 74% of patients with squamous cell anal cancer). Additionally, poliovirus receptor (PVR) expression has been described in several squamous cell carcinomas, and has been correlated with PD-L1 expression and poorer prognosis, suggesting dual inhibition of PVR and PD-L1 as a potential mechanism of overcome the resistance to immune checkpoint monotherapy. Moreover, CRT induces the generation of tumor-neoantigens and could act in synergy with immunotherapy in this setting. The trial hypothesizes that the addition of atezolizumab (anti-PD-L1) and tiragolumab (anti-TIGIT) to chemoradiotherapy may lead to enhanced and more durable responses. Methods: TIRANUS is a Phase II, single-arm, open-label, non-randomized, multicenter clinical trial of atezolizumab and tiragolumab in concomitance with standard CRT as definitive therapy in treatment-naïve, localized squamous cell carcinoma of the anal canal. Patients receive atezolizumab (1200mg) plus tiragolumab (600 mg) for 2 cycles (Q3W) in concomitance with the 6 weeks of CRT (cisplatin: 60 mg/m² on days 1 and 29; 5-FU: 1000 mg/m² per day on days 1-4 and 29-32; radiotherapy: 1.8 Gy per day / total dose 54 Gy). After the concomitant phase, patients receive atezolizumab (1200mg) and tiragolumab (600 mg) Q3W for 6 additional cycles (consolidation phase). The primary endpoint is CCR rate, defined as the percentage of patients who achieve radiological complete response (CR), disappearance of all lesions according to RECIST 1.1 criteria (locally assessed) and no presence of residual disease assessed by biopsy at the end of consolidation phase (week 26). Secondary endpoints include Locoregional failure rate (LFR), Disease-free survival (DFS), Colostomy-free survival (CFS), Overall survival (OS), quality of life, safety and the determination of immune biomarkers potentially predictors of response in blood and tumor samples. Using a precision analysis by Clopper-Pearson method (asymptotic 95% confidence interval) and an expected CCR rate of 85%, a total of 45 evaluable patients are needed to obtain a precision estimation of ±10.4%. Accrual started in February 2023. EudraCT: 2021-005887-24 Clinical Trial identifier: NCT05201612. Clinical trial information: NCT05661188.