biostudies-literatureUnknown5(5)Shi WShanghai Chest Hospital of Shanghai Jiao Tong University School of MedicineShanghai Jiao Tong UniversityThe clinical applications of immunocytokines are severely restricted by dose-limiting toxicities. To address this challenge, here we propose a next-generation immunocytokine concept involving the design of LH05, a tumor-conditional anti-PD-L1/interleukin-15 (IL-15) prodrug. LH05 innovatively masks IL-15 with steric hindrance, mitigating the "cytokine sink" effect of IL-15 and reducing systemic toxicities associated with wild-type anti-PD-L1/IL-15. Moreover, upon specific proteolytic cleavage within the tumor microenvironment, LH05 releases an active IL-15 superagonist, exerting potent antitumor effects. Mechanistically, the antitumor efficacy of LH05 depends on the increased infiltration of CD8⁺ T and natural killer cells by stimulating the chemokines CXCL9 and CXCL10, thereby cCell reports. Medicine101531https://www.ebi.ac.uk/biostudies/studies/S-EPMC11148641biostudies-literatureNext-generation anti-PD-L1/IL-15 immunocytokine elicits superior antitumor immunity in cold tumors with minimal toxicity.PMC11148641Zhou LWu MZeng QJiang LChen JLiu NZhu FShi WSong LHu FLiu ZYang YZhu JLu HFu JGong LWang YfalseNext-generation anti-PD-L1/IL-15 immunocytokine elicits superior antitumor immunity in cold tumors with minimal toxicity.The clinical applications of immunocytokines are severely restricted by dose-limiting toxicities. To address this challenge, here we propose a next-generation immunocytokine concept involving the design of LH05, a tumor-conditional anti-PD-L1/interleukin-15 (IL-15) prodrug. LH05 innovatively masks IL-15 with steric hindrance, mitigating the "cytokine sink" effect of IL-15 and reducing systemic toxicities associated with wild-type anti-PD-L1/IL-15. Moreover, upon specific proteolytic cleavage within the tumor microenvironment, LH05 releases an active IL-15 superagonist, exerting potent antitumor effects. Mechanistically, the antitumor efficacy of LH05 depends on the increased infiltration of CD8⁺ T and natural killer cells by stimulating the chemokines CXCL9 and CXCL10, thereby c2024-01-01T00:00:00Z2024 May2026-06-02T09:05:12.358Z2026-04-16T03:13:05.316ZS-EPMC111486413869710510.1016/j.xcrm.2024.101531