Pharmacologic Activation of STING in the Bladder Induces Potent Antitumor Immunity in Non–Muscle Invasive Murine Bladder Cancer

Abstract

Schweinfurthins, a class of natural products, have attracted considerable interest for novel therapy development because of their selective and potent anti-proliferative activity against human cancer cells. However, the underlying mechanism is not well understood. Herein, we demonstrated that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Intracellularly, schweinfurthins and their analogs arrested trans-Golgi-network trafficking, likely by binding to oxysterol-binding proteins, leading to an effective inhibition of mTOR/AKT signaling through inducing endoplasmic reticulum stress and suppressing both lipid raft-mediated PI3K activation and mTOR/RheB complex formation. Moreover, schweinfurthins were found to be highly potent toward PTEN-deficient B cell lymphoma cells, and displayed two orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in trans-Golgi-network trafficking and linked mechanistically this cellular effect with mTOR/AKT signaling and with cancer cell survival and growth. Our findings suggest a new opportunity to modulate oncogenic signaling by interfering with TGN trafficking to treat mTOR/AKT-dependent human cancers.

The proto-oncogene SRC phosphorylates cGAS to inhibit an antitumor immune response

“…In recent years, strategies of augmenting STING signaling have been the subject of intense investigation for eliciting antitumor immune responses, especially for immunologically “cold” tumors through the activation of tumor-resident myeloid cells and vasculature ( 26 , 28 , 59 , 60 ). The clinical importance of STING-mediated antitumor immunity is perhaps best exemplified by nonmuscle invasive bladder cancer where intravesical immunotherapy with the c-di-AMP–producing bacteria, bacillus Calmette-Guérin (BCG), is a mainstay of treatment ( 61 , 62 ). In preclinical models of urothelial cancer, BCG strains engineered to overproduce c-di-AMP have yielded increased trained immunity, improved tumor clearance, and prolonged survival ( 63 ).…”

The proto-oncogene c-Src phosphorylates cGAS to reduce DNA binding and activation

“…The clinical importance of STING-mediated anti-tumor immunity is perhaps best exemplified by non-muscle invasive bladder cancer where intravesical immunotherapy with the c-di-AMP producing bacteria, BCG, is a mainstay of treatment 62,63 . In pre-clinical models of urothelial cancer, BCG strains engineered to overproduce c-di-AMP have yielded increased trained immunity, improved tumor clearance, and prolonged survival 64 .…”

Advances in preclinical approaches for intravesical therapy of bladder cancer

“…The potential of activating the stimulator of interferon genes (STING) by natural or synthetic agonists has gained attention due to its possibility of triggering immune responses against tumors. This is achieved through the production of type I interferons (IFNs) and inflammatory cytokines [21]. BCG is the established treatment for high-risk NMIBC, but there are limited options for patients who do not respond to BCG [21].…”

“…This is achieved through the production of type I interferons (IFNs) and inflammatory cytokines [21]. BCG is the established treatment for high-risk NMIBC, but there are limited options for patients who do not respond to BCG [21]. Huang and colleagues investigated the effects of E7766, a macrocyclic-bridged STING agonist, administered directly into the bladder, in two mouse models of NMIBC that were Adapted from [19] with permission from Springer Nature.…”

“…resistant to BCG and anti-PD-1 treatments [21]. The study discovered that E7766 effectively stimulated the STING protein, triggering IFNb expression in human immune cells and demonstrating efficacy across various STING genotypes.…”