Researchers at Johns Hopkins have identified a method to convert immune-resistant (“cold”) tumors into those susceptible to immune attack (“hot”), offering a potential new avenue for cancer treatment. The study, published in Nature Immunology, demonstrates that stimulating the tumor microenvironment with specific immune-activating signals can trigger the formation of tertiary lymphoid structures (TLSs), specialized hubs where the body’s defenses coordinate an assault on cancer cells.
The Challenge of ‘Cold’ Tumors
Many cancers evade the immune system, classified as “immune cold” because the body fails to recognize them as a threat. These tumors respond poorly to standard treatments, leading to worse outcomes for patients. The goal of this research was to find a way to overcome this resistance and turn these tumors into targets for the immune system.
This matters because current immunotherapies, such as checkpoint inhibitors, often fail in patients with cold tumors. Boosting immune response within the tumor itself could make these treatments far more effective.
How the ‘Switch’ Works: TLS Formation
The team focused on TLSs, clusters of immune cells that form in areas of chronic inflammation, including in some tumors. The presence of TLSs is strongly linked to better patient survival, as they help organize a focused immune response. The researchers discovered that activating two key proteins – STING and the lymphotoxin-β receptor (LTβR) – simultaneously can induce TLS formation in tumors that previously lacked them.
In laboratory tests on mice, this combined activation triggered a powerful immune response:
- Killer T cells (CD8⁺ T cells) surged into action, suppressing tumor growth.
- New blood vessels (high endothelial venules) formed, allowing immune cells to enter the tumor more easily.
- B cells launched germinal-center reactions, producing long-lasting antibodies and memory cells.
This created a durable, body-wide immune defense capable of preventing cancer recurrence.
Implications for Broad Cancer Treatment
The study suggests that early and combined stimulation of T-cell activity not only kills tumor cells directly but also builds the “immune infrastructure” within tumors, sustaining and amplifying anti-cancer responses. The findings may have broad applicability, potentially enhancing the effectiveness of existing therapies, including both checkpoint inhibitors and traditional chemotherapy.
“By building the right immune infrastructure inside tumors, we can potentiate the patient’s own defenses,” explains Masanobu Komatsu, the lead researcher.
Next Steps and Funding
Komatsu’s team is now further investigating the mechanisms of TLS therapy and preparing for clinical trials in adult and pediatric cancer patients. The research was funded by the National Cancer Institute/NIH, the Department of Defense, and the Florida Department of Health.
The ability to convert cold tumors into hot ones represents a significant step forward in cancer immunotherapy, offering a potential new strategy for improving treatment outcomes across various tumor types.
