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Background Immune checkpoint inhibitors have revolutionized cancer therapy, yet a substantial proportion of patients exhibit primary or acquired resistance. Immunocytokines offer a strategy to enhance antitumor immunity by delivering cytokine signals selectively to the tumor microenvironment. Here, we describe the immunoconjugate anti-programmed cell death protein 1 (PD-1)-interleukin (IL)-18 (aPD1-IL18 mut), designed to couple PD-1-blockade with localized IL-18-mediated immune activation.Methods aPD1-IL18 mut was generated by chemically conjugating the anti-human PD-1 antibody Lipustobart to an IL-18 variant engineered to evade IL-18 binding protein. Its mechanism of action was characterized using human PD-1 transgenic mouse models. To assess the translational relevance of these in vivo findings, complementary in vitro assays were conducted on human tumor samples, alongside analyses of publicly available single-cell RNA sequencing datasets.Results In vitro, PD-1 engagement enhanced functional IL-18 activity, preserving interferon (IFN)-γ secretion even under IL-18BP pressure. In MC38 tumors, aPD1-IL18 mut induced robust CD8+ T cell-driven tumor control, accompanied by intratumoral accumulation of activated CD8+ T cells and a pronounced type 1-associated cytokine response. In anti-PD-1-resistant YUMM1.7 tumors, therapeutic efficacy instead relied predominantly on Th1-like CD4+ effector T cells, and aPD1-IL18mut stimulation was associated with enhanced activation, proliferation, IFN-γ, and granzyme B expression in PD-1+IL-18Rɑ+ CD4+ T cells. In human cancer digest cultures, aPD1-IL18mut elicited a dominant IL-18/IFN-γ-driven cytokine signature and enhanced tumor cell killing. Importantly, analyses of the immune infiltrate across multiple human solid tumor types identified analogous PD-1+IL-18Rɑ+ CD4+ Th1-like and CD8+ effector-like T-cell subsets with effector-associated and tumor-reactive transcriptional and protein signatures.Conclusions aPD1-IL18 mut activates T-cell populations with tumor-reactive features and promotes IFN-γ-driven inflammation across distinct tumor immune contexts. Its ability to activate CD8+ and CD4+ Th1-like effector cells, together with the presence of analogous subsets in multiple human cancers, provides mechanistic and translational support for PD-1-targeted IL-18 therapy.