Background: Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC) are the most prevalent non-melanoma skin cancers. Photodynamic Therapy (PDT) is an established, non-invasive treatment known for its favorable cosmetic results, especially in superficial lesions. However, its limited penetration restricts effectiveness against thicker or more aggressive tumors, prompting the development of combination strategies to enhance PDT's efficacy.

Methods: This narrative review examines studies published from 2015 to 2025 that explore combining PDT with other treatments for BCC and SCC. A systematic search identified clinical trials, cohort studies, and case reports focusing on combinations with immunotherapy, chemotherapy, physical debulking, nanotechnology, and pharmacologic agents. The analysis considered treatment outcomes, safety, mechanistic insights, and therapeutic synergy.

Results: Combination treatments showed improved tumor clearance rates, reduced recurrence, and enhanced immune responses. Immunomodulators and immune checkpoint inhibitors boosted the immune effects of PDT. Topical chemotherapy, like fluorouracil, enhanced photosensitizer uptake and lesion clearance. Mechanical techniques, such as curettage or laser ablation, improved cure rates for nodular BCC. Nanoparticle delivery systems enabled deeper tissue penetration, while agents like vitamin D analogues and mTOR inhibitors increased tumor sensitivity to PDT. Importantly, these combinations preserved cosmetic outcomes while expanding efficacy for more aggressive lesions.

Conclusion: Integrating PDT with immunological, chemical, physical, or nanotechnological approaches represents a significant advancement in non-melanoma skin cancer treatment. These combinations overcome traditional monotherapy limitations and maintain cosmetic benefits. Future large-scale trials are crucial to refine protocols, validate long-term outcomes, and encourage routine clinical implementation.