Immunotherapy has caused a paradigm shift in the treatment of several malignancies, particularly the blockade of programmed death‐1 (PD‐1) and its specific receptor/ligand PD‐L1 that have revolutionized the treatment of a variety of malignancies, but significant durable responses only occur in a small percentage of patients, and other patients failed to respond to the treatment. Even those who initially respond can ultimately relapse despite maintenance treatment, there is considerable potential for synergistic combinations of immunotherapy and chemotherapy agents with immune checkpoint inhibitors into conventional cancer treatments. The clinical experience in the use of cytokines in the clinical setting indicated the efficiency of cytokine therapy in cancer immunotherapy. Combinational approaches to enhancing PD‐L1/PD‐1 pathways blockade efficacy with several cytokines such as interleukin (IL)‐2, IL‐15, IL‐21, IL‐12, IL‐10, and interferon‐α (IFN‐α) may result in additional benefits. In this review, the current state of knowledge about PD‐1/PD‐L1 inhibitors, the date in the literature to ascertain the combination of anti‐PD‐1/PD‐L1 antibodies with cytokines is discussed. Finally, it is noteworthy that novel therapeutic approaches based on the efficient combination of recombinant cytokines with the PD‐L1/PD‐1 blockade therapy can enhance antitumor immune responses against various malignancies.

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Introduction: Due to their unique properties including cellular uptake and the delivery efficiency to biological systems, nanoparticles are used in various preclinical and clinical applications. The aim of this study was to investigate the toxicity impacts of zinc oxide nanoparticles (ZnO-NPs) on morphology and functionality of the ratʼs liver and spleen and illustrated its safe-therapeutic doses.Methods: The 28 female Swiss albino rats (180-220 g) and two human hepatocyte cell lines (HepG2 and HUH7) were designed as an in vivo and in vitro study, respectively.Samples were treated with certain doses of ZnO-NPs. The ratʼs liver morphology and functionality and apoptotic genes expression profile (Bax, Bcl-2, and P53) were analyzed to detect the cytotoxicity and antitumor impacts of ZnO-NPs, respectively. Results:The results showed a positive significant association between the increasing doses of ZnO-NPs and alanine aminotransferase/aspartate aminotransferase values.Moreover, a meaningful correlation was detected between the ratʼs liver and spleen weight and ZnO-NPs doses. Furthermore, the histopathological analysis of ratʼs liver showed the individual cytotoxic properties of ZnO-NPs. Finally, the positive significant correlation was detected among the expression of Bax and P53 genes with ZnO-NPs. In addition, the negative correlation was demonstrated between the expression of Bcl-2 and ZnO-NPs. Conclusion:In general, in the current study, the antitumor effects of ZnO-NPs were confirmed by the enhancement of P53 and Bax genes expression profile, which are indicated the apoptotic induction in HUH7 cell line. Moreover, we introduced a safeclinical ZnO-NPs dosage, have antitumor effects.

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