Breakthrough in bacterial immunotherapy: ACTM-838 targets solid tumors
Solid tumors have long posed a challenge for immunotherapy, often creating an immune-suppressive microenvironment that thwarts even the most advanced treatments. A new study published in Oncotarget (Volume 16, October 6, 2025) introduces ACTM-838, a novel systemically delivered bacterial immunotherapy designed to enrich in solid tumors and deliver potent immune payloads. Led by first author Kyle R. Cron and corresponding author Akshata R. Udyavar, researchers from Actym Therapeutics report that ACTM-838 safely delivers immune-activating proteins directly to tumors, potentially offering a new option for patients whose solid tumors resist existing therapies.
How ACTM-838 works: a targeted, dual-payload approach
ACTM-838 is built on a modular, genetically engineered live attenuated Salmonella Typhimurium platform named STACT. This design enables tissue-specific localization and the systemic delivery of multiplexed payloads to the tumor microenvironment (TME). Inside the tumor, ACTM-838 releases two key immune-stimulating components: IL-15 paired with its receptor IL-15Rα, and a modified cyclic dinucleotide that activates the STING pathway. Together, these payloads engage both innate and adaptive immunity, reprogramming the TME from immune-suppressive to immune-permissive and enabling robust anti-tumor responses.
Safety and tumor specificity: reducing collateral damage
A central hurdle in bacterial therapies is avoiding harm to healthy tissues. The ACTM-838 platform demonstrated tumor-specific localization after intravenous administration, with markedly reduced inflammatory toxicity compared with the parent bacterial strain. This enhanced safety profile is crucial for translating bacterial immunotherapies into clinical settings, where systemic toxicity can limit broader use.
Immune remodeling in the tumor microenvironment
In preclinical models, ACTM-838 reshaped the immune cell landscape within tumors. Researchers observed an increase in cytotoxic T-cells and antigen-presenting macrophages—cells essential for recognizing and attacking cancer cells. At the same time, suppressive populations such as regulatory T-cells and exhausted T-cells declined. These shifts were corroborated by genetic analyses and cellular assays, indicating a coordinated shift toward a more effective anti-tumor immune response.
Promising anti-tumor activity and durable memory
ACTM-838 not only shrank tumors in preclinical tests but also prevented recurrence after treatment. Mice cured of tumors resisted re-injection with cancer cells, suggesting the establishment of durable immune memory. Importantly, ACTM-838 showed strong synergy with anti-PD1 therapy, a mainstay of cancer immunotherapy, leading to improved outcomes in both treatment-resistant and responsive tumor models.
Clinical potential and next steps
The study presents proof-of-concept that a live bacterial therapy can safely and effectively deliver gene-based immune modulators directly to tumors. ACTM-838’s favorable safety signals and its ability to enhance both innate and adaptive immune responses support its progression to clinical evaluation. A Phase I clinical trial is now underway to assess safety, tolerability, and preliminary efficacy in patients with solid tumors.
Implications for future cancer treatments
If confirmed in humans, ACTM-838 could expand the range of patients who benefit from immunotherapy, particularly those with tumors less responsive to checkpoint blockade. By reprogramming the tumor milieu and fostering lasting immune memory, this approach may complement existing therapies and offer durable disease control where other strategies falter.
Conclusion
ACTM-838 represents an innovative convergence of microbiology and cancer immunotherapy. Through precise tumor targeting, reduced toxicity, and a powerful dual-payload strategy, this engineered Salmonella therapy has the potential to redefine treatment paradigms for solid tumors and deliver durable anti-tumor immunity.
