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Cancer Cells Exploit Immune Pathways to Resist Drugs

In cancer immunotherapy, the spotlight has fallen on STING as a pivotal target of recent interest. Biopharmaceutical companies worldwide are vigorously developing innovative therapies targeting STING with the goal of activating immune pathways to combat cancer cells.

While these STING agonists have demonstrated promise in preclinical studies, a perplexing phenomenon has emerged in certain clinical trials. Contrary to expectations, drugs designed to activate the STING pathway have not consistently yielded the desired benefits for advanced cancer patients. For instance, a Phase 1 clinical trial assessing STING agonists reported only one out of 47 patients with advanced or metastatic cancer displaying a definitive partial response. In another Phase 1 clinical trial involving a STING agonist co-administered with a PD-1 inhibitor, the overall remission rate for advanced cancer patients hovered around 10%.

So, what accounts for the unexpected outcomes of STING agonists in the fight against cancer? In their quest for answers, researchers at the Memorial Sloan Kettering Cancer Center, in collaboration with Weill Cornell Medicine, have uncovered a counterintuitive possibility—drugs inhibiting STING activation may prove more beneficial to patients with advanced cancer than STING activators.

This revelation hinges on the nature of the STING signaling pathway itself. Within the human body, the presence of double-stranded DNA molecules in the cytoplasmic matrix serves as an early warning signal, indicating the intrusion of pathogens, the existence of cancer cells, or cell rupture. Once intracellular sensors detect cytoplasmic DNA, they activate the STING protein, which, in turn, triggers the expression of inflammation-associated genes, igniting an innate immune response that shields the body from foreign invaders and abnormal cells—a pivotal process in anti-tumor immunity.

However, the new study suggests that cancer cells disrupt the STING signaling pathway, creating an immunosuppressive tumor microenvironment. Particularly in advanced cancer stages, where cancer cells exhibit high chromosomal instability, the STING pathway remains persistently active, leading to "desensitization." This, in turn, rewires the downstream signaling pathway, inducing endoplasmic reticulum stress—a favorable environment for cancer cell metastasis.

Dr. Samuel Bakhoum, co-corresponding author of the study, analogizes this phenomenon, "think of STING signaling as a car alarm. If it rarely sounds, the loud noise will grab your attention. But if it keeps going off, you become accustomed to it and tune it out."

To understand the interactions between cancer cells and immune cells in the tumor microenvironment, another co-corresponding author, Dr. Ashley Laughney, led the team in developing a specialized computational tool named "Contact Tracing". This tool predicts cell-cell interactions and assesses how ligand-receptor interactions influence signal-receiving cells based on single-cell sequencing data.

Dr. Laughney highlights a significant discovery, "one of our most crucial findings is that altering the degree of chromosomal instability or activating STING significantly changes the response within the tumor and its surroundings."

The researchers confirmed the link between chromosomal instability-driven cancer cell metastasis and STING signaling in mouse models implanted with various tumor cells, as well as in human healthy cells and tumor samples. These findings also open the door to innovative therapeutic concepts—for advanced cancer patients with chromosomal instability, activating STING may prove ineffective due to cellular desensitization". In such cases, inhibiting STING could be a promising alternative.

In experimental settings, the researchers administered STING inhibitors to mouse models of melanoma, breast cancer, and colorectal cancer, effectively reducing metastasis driven by chromosomal instability.

Additionally, these insights suggest that by identifying tumors still capable of robust responses to STING activation, clinicians can select patients who would genuinely benefit from STING agonist therapy.