Why Do STING Agonists Show Poor Anticancer Efficacy?

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Why Do STING Agonists Show Poor Anticancer Efficacy?

For decades, scientists have been searching for more effective and durable cancer treatment methods.

The STING pathway has emerged as a crucial regulator of immune responses against viruses and bacteria, contributing to antitumor immunity.

Several STING agonists have entered clinical research, making the activation of the STING pathway a promising approach for cancer treatment.

However, while STING agonist drugs have shown great promise in preclinical studies, their performance in clinical trials has been disappointing.

On August 24, 2023, a team led by Dr. Samuel Bakhoum at the Sloan Kettering Cancer Center, published a research paper titled “Non-cell-autonomous cancer progression from chromosomal instability” in the journal Nature.

Why Do STING Agonists Show Poor Anticancer Efficacy?

This study introduced a novel single-cell RNA sequencing data analysis technique called ContactTracing, which confirmed that chronic activation of the STING pathway induced by chromosomal instability (CIN) leads to downstream changes in cell signaling.

This downstream signaling reconnection inhibits effective antitumor immunity by attracting cells that suppress immune responses within and around the tumor, creating a “prometastatic tumor microenvironment,” thus aiding cancer metastasis.

This discovery helps explain why STING agonist drugs have shown poor results in clinical trials for late-stage cancer patients.

Additionally, the study suggests a biomarker-based approach to identify which patients might benefit from STING activation and which ones might benefit from STING inhibition.

Chromosomal instability (CIN) is a hallmark of cancer, particularly in late-stage cancers, where the normal cell division process goes awry.

CIN is a significant driver of cancer treatment resistance, spread, and metastasis.

The STING pathway triggers a strong inflammatory response to protect the body from invading bacteria, viruses, and unhealthy cells.

Previous research by this team found that chromosomal instability induces a cytoplasmic double-stranded DNA (dsDNA) response in tumor cells through the cGAS-STING innate immune pathway, promoting tumor metastasis.

However, it was unclear whether the impact of chromosomal instability on tumor progression was cell-autonomous or relied on the immune system.

Additionally, it was unclear how chromosomally unstable tumors adapt to chromosomal instability and evade immune surveillance triggered by cGAS-STING activation and downstream type I interferon response.

Dr. Samuel Bakhoum, a co-corresponding author of the paper, stated that substantial funding has been invested in the development of anticancer drugs based on STING pathway activation.

While these candidate drugs have shown promise in the lab, they haven’t demonstrated significant anticancer effects in clinical trials so far.

For instance, in a clinical trial involving 47 patients with STING agonists, only 2 showed partial relief from cancer.

In another trial involving over 100 patients, the overall response rate for a combination of STING agonists and immunotherapy was just 10%.

So, why do STING agonists appear promising in preclinical research but fall short in clinical settings?

In this latest study, the research team developed a novel single-cell RNA sequencing data analysis technique called ContactTracing to examine how growing tumor cells respond to stimuli at the single-cell transcriptome level.

This went beyond just recording whether one cell can interact with another and allowed them to study if and how these interactions affect cell signaling.

Using ContactTracing, the team explored the roles of different cells in the tumor microenvironment, discovering that chronic activation of the cGAS-STING pathway induced by chromosomal instability promoted the reconnection of downstream signals in cancer cells, leading to a pro-metastatic tumor microenvironment.

This reconnection manifested as a selective downstream type I interferon response to STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response.

Reversing chromosomal instability, eliminating STING in cancer cells, or inhibiting the ER stress response signal effectively eliminated the tumor microenvironment’s dependence on chromosomal instability and suppressed tumor metastasis in immunocompetent environments, with no impact in severely immunocompromised settings.

Why Do STING Agonists Show Poor Anticancer Efficacy?

ContactTracing finds that endoplasmic reticulum stress is the main mediator of CIN-induced immunosuppression

ContactTracing identified ER stress as the primary mediator of CIN-induced immune suppression in melanoma, breast cancer, and colorectal cancer models.

This research provides a feasible strategy for identifying and treating tumors driven by chromosomal instability-induced inflammatory stimuli.

The research team suggests that this study offers an opportunity for improving treatment for many late-stage cancer patients driven by chromosomal instability.

The ineffectiveness of STING agonists in these cancer patients may be due to sustained activation of the STING pathway induced by chromosomal instability, which desensitizes patients to STING agonists.

Therefore, counterintuitively, STING inhibitors might be effective for these patients.