[Introduction] Molecular targeted drugs and immune checkpoint inhibitors (ICIs) are designed to act specifically on tumor-target molecules. Intra-arterial (IA) administration via tumor-feeding arteries is theoretically a highly efficient delivery method. [Basic Research] Using mouse bearing head and neck cancer cell lines, we evaluated the anti-tumor immunological effects of: (1) saline, (2) systemic 100 µg Nivolumab, and (3) local 10 µg Nivolumab. Both (2) and (3) showed significant tumor inhibition compared to (1). Furthermore, the infiltration of CD8+ T cells in (3) was equivalent to (2), demonstrating the efficacy of low-dose local Nivolumab administration (JP Patent 2024-102980; Anticancer Res. 2022). [Clinical Research] A first-in-human clinical trial of IA immunotherapy was conducted (jRCTs041220157). A 67-year-old female with p16-positive oropharyngeal cancer (T4N2M1), previously treated with Pembrolizumab, underwent the procedure. A catheter was inserted via the superficial temporal artery into the tumor-feeding artery, and IA Nivolumab (20 mg ~ 2 doses) was administered. Successful binding of Nivolumab to tumor-infiltrating lymphocytes was observed even at the 20 mg IA dose (Patent Pending 2024-102980). Following additional treatment, the patient achieved a complete response (CR). [Development of Intra-arterial Photoimmunotherapy (PIT)]The currently approved protocol for Cetuximab Sarotalocan Sodium (Akalux®) requires an IV infusion of 640 mg/m² over 24 hours, followed by laser irradiation under general anesthesia the next day. Our refined protocol involves IA administration of Akalux® at 1/100 to 1/10 of the standard dose, followed by immediate laser irradiation under local anesthesia, with subsequent outpatient IV Pembrolizumab seven days later. This innovative method has reached an agreement with the PMDA regulatory authority, and an investigator-initiated Phase I/II clinical trial has been approved by AMED with a budget of 2 million dollars.