With a new study in the journal Scientific Bulletinresearchers at Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University have discovered a new way aggressive breast cancer cells escape the immune system’s defenses. This discovery also reveals a potential weakness that could make these tumors particularly sensitive to existing immunotherapies.
Many cancer cells are known to have high levels of DNA damage, and pieces of DNA can leak into the cell’s cytoplasm. This activates an alarm system called the cGAS-STING pathway, which triggers an immune response to attack the tumor. However, researchers show that some tumors fight back using a specific molecule called FAM83H-AS1. This molecule acts like a switch, tripping the body’s alarm system. It switches the immune response from a strong antitumor attack to a state of chronic pro-tumor inflammation. This shift helps the cancer create an immunosuppressive tumor microenvironment, allowing it to grow.
Mainly, this trick creates a big vulnerability. The same inflammatory process that protects the tumor also causes it to produce high levels of a protein called PD-L1, a key target of cancer immunotherapy drugs. As a result, tumors become highly sensitive to immunotherapy drugs designed to block PD-L1. The research suggests that patients with tumors that overexpress FAM83H-AS1 could be ideal candidates for these existing therapies.
FAM83H-AS1 is a long non-coding RNA (lncRNA), located on chromosome 8q24, a region often associated with cancer risk – but considered a “desert gene” because this large region contains very few protein-coding genes. Although the MYC oncogene is present nearby, MYC expression is not altered in some tumors, which is insufficient to explain the high risk of developing various tumors.
It is very likely that this region harbors important oncogenes that have yet to be discovered.”
Man-Li Luo, Principal Investigator of the study, Professor and Associate Director of Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
While lncRNAs far outnumber protein-coding genes in the human genome, their functions are often poorly understood, obscuring their potential significance. An example is lncRNA FAM83H-AS1. Despite clear evidence linking its overexpression to poor prognosis in a wide range of cancers, the molecular mechanism driving its role in tumor progression has remained unknown.
The research team discovered that FAM83H-AS1 is frequently amplified and is particularly active in tumor tissues. High levels of this RNA molecule are associated with reduced anti-tumor immunity and lower survival rates in breast cancer patients. The important thing is that they clarify how it works. Researchers reveal that FAM83H-AS1 hijacks a critical signaling pathway known as cGAS-STING. Rather than triggering a strong antitumor interferon response, high levels of FAM83H-AS1 shift pathway signaling toward a pro-neoplastic inflammatory response driven by NF-κB. This switch effectively disarms the body’s natural defenses, turning immune attacks into cancer-fueling inflammation.
These findings establish FAM83H-AS1 as a key oncogene in the chromosome 8q24 region. The term “gene desert” is only desert for protein-coding genes, not for functional non-coding elements such as this central lncRNA. There are more “dark forests” of non-coding regulation waiting to be explored in genomes.
Since overexpression of FAM83H-AS1 has been linked to poor prognosis in many cancers, the researchers believe that its immune evasion mechanism may not be limited to breast cancer. Their work also points directly to a therapeutic insight—tumors characterized by FAM83H-AS1 overexpression or subsequent NF-κB activation may be particularly vulnerable to checkpoint blockade therapy.
