Sensitizing Tumors to Immune Checkpoint Blockage via STING Agonists Delivered by Tumor-Penetrating Neutrophil Cytopharmaceuticals

Immune checkpoint inhibitors (ICIs) have displayed potential efficacy in triple-negative breast cancer (TNBC) treatment, while only a minority of patients benefit from ICI therapy currently. Although activation of the innate immune stimulator of interferon genes (STING) pathway potentiates antitumor immunity and thus sensitizes tumors to ICIs, the efficient tumor penetration of STING agonists remains critically challenging. Herein, we prepare a tumor-penetrating neotype neutrophil cytopharmaceutical (NEs@STING-Mal-NP) with liposomal STING agonists conjugating on the surface of neutrophils, which is different from the typical neutrophil cytopharmaceutical that loads drugs inside the neutrophils. We show NEs@STING-Mal-NP that inherit the merits of neutrophils including proactive tumor vascular extravasation and tissue penetration significantly boost the tumor penetration of STING agonists. Moreover, the backpacked liposomal STING agonists can be released in response to hyaluronidase rich in the tumor environment, leading to enhanced uptake by tumor-infiltrating immune cells and tumor cells. Thus, NEs@STING-Mal-NP effectively activate the STING pathway and reinvigorate the tumor environment through converting macrophages and neutrophils to antitumor phenotypes, promoting the maturation of dendritic cells, and enhancing the infiltration and tumoricidal ability of T cells. Specifically, this cytopharmaceutical displays a significant inhibition on tumor growth and prolongs the survival of TNBC-bearing mice when combined with ICIs. We demonstrate that neutrophils serve as promising vehicles for delivering STING agonists throughout solid tumors and the developed neutrophil cytopharmaceuticals with backpacked STING agonists exhibit huge potential in boosting the immunotherapy of ICIs

Novel β‑Carboline/Hydroxamic Acid Hybrids Targeting Both Histone Deacetylase and DNA Display High Anticancer Activity via Regulation of the p53 Signaling Pathway

A novel series of hybrids from β-carboline and hydroxamic acid were designed and synthesized. Several compounds (<b>5m</b>, <b>11b</b>–<b>d</b>, and <b>11h</b>) not only exerted significant antiproliferation activity against four human colorectal cancer (CRC) cell lines but also showed histone deacetylase inhibitory effects in vitro. The most potent compound, <b>11c</b>, exhibited anticancer potency sevenfold higher than that of SAHA. <b>11c</b> triggered more significant cancer cell apoptosis than did SAHA by cleavage of both PARP and caspase 3 in a dose-dependent manner. Furthermore, <b>11c</b> simultaneously increased the acetylation of histone H3 and α-tubulin, enhanced expression of DNA damage markers histone H2AX phosphorylation and p-p53 (Ser15), and activated p53 signaling pathway in HCT116 cells. Finally, <b>11c</b> showed low acute toxicity in mice and inhibited the growth of implanted human CRC in mice more potently than did SAHA. Together, <b>11c</b> possessed potent antitumor activity and may be a promising candidate for the potential treatment of human CRC