INTRODUCTION: Lymphopenia induced by radiotherapy or chemotherapy can promote homeostatic proliferation of residual or adoptive lymphocytes, potentially enhancing antitumor immunity. However, this immunity diminishes rapidly with tumor progression, and the underlying mechanisms remain unclear. This study investigates the role of PD-1 signaling in homeostatic proliferation-induced antitumor immunity in malignant melanoma. METHODS: We evaluated T-cell dynamics in lymphopenic mice, analyzing PD-1 expression, IFN-γ production by CD8 RESULTS: Although T cells proliferated continuously in lymphopenic mice, IFN-γ+ CD8 DISCUSSION: These findings indicate that the PD-1/PD-L1 axis plays a critical role in immune tolerance during homeostatic proliferation. Anti-PD-1 therapy may enhance antitumor immunity during lymphopenia recovery after chemotherapy or radiotherapy, offering a potential strategy to sustain T-cell-mediated tumor control.