Understanding tumor microenvironment dynamics and immune checkpoint inhibitor efficacy following mEGFR-targeted near-infrared photoimmunotherapy.

Near-infrared photoimmunotherapy (NIR-PIT) is an innovative cancer treatment that provides both direct and selective killing of cancer cells and enhancement of the host's antitumor immune response. In Japan, EGFR-targeted NIR-PIT is already used clinically for head and neck cancer; however, there is limited understanding of the immune response kinetics of EGFR-targeted NIR-PIT. This limitation poses a significant barrier to further development of NIR-PIT, such as expanding its applications to other cancers and combination therapies. The purpose of this study is to establish a model incorporating EGFR-targeted NIR-PIT using a new anti-mouse EGFR (mEGFR) antibody and to evaluate its potential in an immunocompetent model. Employing a syngeneic tumor expressing mEGFR, mEGFR-targeted NIR-PIT showed significant tumor suppression in both the LL/2-luc and TS/A models, with the latter also showing improved survival. Analysis of the host immune response after NIR-PIT in the TS/A model indicated a temporary early increase in dendritic cell maturation markers, followed by a rise in intratumoral CD8+ T cells from day three after treatment. Combining CTLA-4 blockade therapy with mEGFR-targeted NIR-PIT resulted in strong tumor growth inhibition and prolonged survival in both models. Notably, the group received early CTLA-4 therapy, which aligns with the timing of immune activation after NIR-PIT, demonstrated better antitumor effect than the group receiving late CTLA-4 therapy. In summary, this mEGFR-targeted NIR-PIT model enabled detailed analysis of NIR-PIT-mediated immune effects and facilitated the establishment of the optimal treatment schedule for CTLA-4 blockade. This preclinical NIR-PIT model would provide valuable insights into improving treatment strategies.