Photodynamic therapy to treat cancers promises the opportunity to delivery focused activation leading to the generation of cytotoxic radical oxygen species with an acceptable safety profile. Commensurate with direct tumour cell killing is the collateral stimulation of host immune responses. The ability to deliver photo-activation presents challenges regarding clinical tractability: - which patients to treat, what cancers and the most reasonable path to test agents in patients. We have developed a mouse model for anal carcinogenesis that faithfully recapitulates the human disease including the predominant associated PIK3CA gene mutation. Cell lines from these mouse anal squamous cell carcinomas (SCCs) form tumours in immune competent, syngeneic mice. As these tumours grow when injected subcutaneously, they are amendable to the topical application of a novel photodynamic therapy using a next generation compound, INV043. Clinically, SCCs can be divided into human papilloma virus (HPV) positive and negative: - the latter category is the most difficult to treat. The anal SCC model reported here is HPV-ve. When INV043 is used alone some tumour control is evident but when combined with immunotherapy checkpoint-blockade (anti-PD1) 80% of mice eliminate the tumours masses and show no evidence of residual tumour cells. Anti-PD1 alone cured 12% of mice with established tumour. Evidence of superior immune cell recruitment with anti-PD1 combined with INV043 led to complete, scar-free tumour resolution. Based on these data we propose to develop a Phase 1 safety trial (PHOTOCHECK) to treat patients with relapse anal SCCs prior to salvage surgery. Ten patients (HPV+/-) would be recruited over 2 years. A pretreatment biopsy will be taken prior to two rounds of photodynamic therapy (over 3-days) and two rounds (3-weeks apart) of anti-PD1 antibody. Tumours will be monitored for one month prior to surgery. This plan allows an assessment of pathological responses along with immunological changes.