After more than a decade of research, an international team led by CEU USP has identified a previously hidden mechanism that helps to regulate the body's immune defences. The study, published in Cell Communication and Signaling, reveals that the protein STING does far more than trigger antiviral responses during infection. It also acts as a sensor of calcium fluctuations and endoplasmic reticulum stress. The findings reshape our understanding of innate immunity, the body's first line of defence against disease.
The role of innate immunity
Innate immunity is the body's rapid-response defence system, present from birth in all living organisms. It provides protection against the vast majority of infectious threats we encounter every day. Unlike adaptive immunity—which produces pathogen-specific antibodies and T cells over the course of days or weeks—innate immunity determines within minutes whether a cell should enter a defensive state and mount an immediate response against an invading pathogen.
The study shows that innate immune responses can be activated not only through the detection of pathogen-derived molecules, but also through purely cellular processes. Specifically, the researchers found that calcium influx into cells, when combined with endoplasmic reticulum stress—a condition that arises when cells are required to produce large amounts of protein—can activate this immune pathway independently of infection.
These mechanisms were demonstrated experimentally using compounds unrelated to infectious agents, including thapsigargin and combinations of DTT and ionomycin, all of which were able to induce antiviral states in treated cells.
“What fascinated us most was seeing that cells continued to respond even after viral sensing pathways had been eliminated using CRISPR, unless STING itself was removed,” explains Dr Sergio Rius-Rocabert, the first author of the study. “STING is best known for coordinating immune responses when DNA appears where it should not, such as during infection or chromosomal instability associated with cancer. That observation suggested we were looking at an alternative STING-dependent signalling pathway that had gone unnoticed until now.”
The significance of this discovery extends well beyond a laboratory observation. Innate immunity not only provides immediate protection against infection but also directs and shapes subsequent adaptive immune responses. Calcium signalling, meanwhile, plays a central role in a wide range of biological processes, including lymphocyte activation, nuclear signalling and muscle contraction.
The researchers propose that this newly identified calcium-dependent pathway may help establish antiviral protection in these critical cell types. Because calcium is a key messenger involved in lymphocyte activation, muscle contraction and neuronal signalling, the mechanism may also prime cells to respond more effectively to pathogen attack.
The findings could help explain why certain neuromuscular disorders are characterised by chronic inflammation despite the absence of an active infection.
For Dr Estanislao Nistal Villán, head of the Virology and Innate Immunity Group at CEU USP, this calcium-driven STING “switch” opens up promising therapeutic possibilities.
“Understanding how this pathway operates in both healthy and disease states is essential if we are to better understand how the body prepares itself to combat infection. Being able to modulate this pathway could allow us to dampen harmful inflammation in autoimmune diseases, while also boosting immune responses in a controlled manner for cancer therapies, improved vaccines and new treatments against infectious diseases.”
International collaboration
The study is the result of a collaboration between CEU USP, the Carlos III Health Institute, the Icahn School of Medicine at Mount Sinai in New York, the National Centre for Biotechnology of the Spanish National Research Council (CNB-CSIC), and the University of Chicago.
Article reference
Rius-Rocabert, S., et al. “Non-canonical STING activation by calcium influx paired to endoplasmic reticulum stress.” Cell Communication and Signaling (2026).