Search

Despite the remarkable success of immune checkpoint inhibitors (ICIs), primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment (TME). Oncolytic viruses (OVs) can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts. Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy. According to the diverse immune cell landscapes among different types of tumors, we rationally and precisely generated three recombinant oncolytic adenoviruses (OAds): OAd-SIRPα-Fc, OAd-Siglec10-Fc and OAd-TIGIT-Fc. These viruses were designed to locally deliver SIRPα-Fc, Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47, CD24 or CD155, respectively, in the TME to achieve enhanced antitumor effects. Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors, while OAd-TIGIT-Fc showed the best antitumor immunity in CD8 + T-cell-dominated tumors. Importantly, the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory. In addition, the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME. In summary, rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer., (© 2023. The Author(s).)

In situ vaccination is a desirable strategy for cancer immunotherapy due to its convenience and capacity to target tumor antigens. Here, an in situ nanovaccine based on a cationic peptide with cholesterol-modified, DP7-C, for cancer immunotherapy is rationally designed, and developed a cancer nanovaccine that is easy to preparate. The nanovaccine includes cocktail small interfering RNAs (siRNAs) and immunologic adjuvant CpG ODNs, has synergistic effect in the cancer treatment. This nanovaccine can induce tumor cell death, promote antigen presentation and relieve immune suppression in the tumor microenvironment (TME). Moreover, this nanovaccine is administered to CT26 (hot) and B16F10 (cold) tumor model mice, in which it targeted the primary tumors and induced systemic antitumor immunity to inhibit metastasis. It is validated that the nanovaccine can convert cold tumors into hot tumors. Furthermore, the nanovaccine increased the immune response to anti-PD-1 therapy by modulating the TME in both CT26- and B16F10-tumor-bearing mice. The siRNA cocktail/CpG ODN/self-assembling peptide nanovaccine is a simple and universal tool that can effectively generate specific tumor cell antigens and can be combined with immuno-oncology agents to enhance antitumor immune activity. The versatile methodology provides an alternative approach for developing cancer nanovaccines., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

MicroRNAs can regulate a variety of physiological and pathological processes and are increasingly recognized as being involved in regulating the malignant progression of cancer, which is an important direction for the study and treatment of cancer. In addition, the tumor microenvironment has gradually become an important direction of study for combating cancer. Researchers can inhibit tumor growth by remodeling and suppressing an immunosuppressive phenotype in the tumor microenvironment. Therefore, the combination of microRNA delivery and tumor microenvironment remodeling may be a potential research direction. In a previous study, we developed a novel cationic and hydrophilic antimicrobial peptide, DP7, by computer simulation. It was found that cholesterol-modified DP7 (DP7-C) has dual functions as a carrier and an immune adjuvant. In this experiment, we used DP7-C to deliver microRNAs or inhibitors intratumorally, where it played a dual role as a carrier and an immune adjuvant. As a delivery vector, DP7-C has more advantages in terms of transfection efficiency and cytotoxicity than Lipo2000 and PEI25K. Components of the DP7-C/RNA complex can effectively escape endosomes after uptake via caveolin- and clathrin-dependent pathways. As an immune adjuvant, DP7-C can activate dendritic cells and promote macrophage polarization. Moreover, it can transform the immunosuppressive tumor microenvironment into an immune-activated tumor microenvironment, indicating its potential as an anticancer therapy. In conclusion, this study identifies a novel microRNA and inhibitor delivery system that can remodel the tumor microenvironment and introduces an alternative scheme for antitumor treatment.