Gut Microbiota-Derived Molecule May Enhance Immunotherapy Response in Lung Cancer

Immunotherapy has transformed the treatment landscape for lung cancer, particularly through immune checkpoint inhibitors (ICIs) that reinvigorate the body’s antitumor immune response. Despite their promise, the majority of patients fail to benefit from these therapies, highlighting a critical unmet need.

New research from the University of Florida (UF) Health suggests that a molecule derived from gut bacteria could significantly enhance immunotherapy responsiveness in lung cancer, offering a potential new strategy to improve outcomes without adding invasive treatments.^1-3

Limited Response Rates Remain a Major Challenge in Immunotherapy

ICIs have emerged as a new standard for many patients with non–small cell lung cancer; however, the response rates achieved remain limited. In a variety of cancers, few patients benefit sustainably, while a number suffer adverse effects (AEs) but no actual benefit.³ These limitations emphasize a need to better understand the underlying biology that could affect this response, such as how the gut microbiome could affect systemic immunity.

“Across all cancers, only about 20% of patients who receive ICIs respond to them—80% do not—so anything that could boost responsiveness is a blockbuster drug,” first study author Rachel Newsome, PhD, a postdoctoral associate in the lab of Christian Jobin, PhD, said in a news release. She added that the ultimate goal is to make immunotherapy more effective for a broader population, noting, “We want to empty those cancer center parking lots that are so full right now.”¹

Identifying a Microbiota-Derived Immune Booster

In a study published in Cell Reports Medicine, UF researchers outlined a methodical strategy to seek out microbiota-derived molecules that could be used to complement the effects of immunotherapy.² They created a multistep discovery pipeline that is able to purify bacterial molecules, assess their ability to stimulate the immune system, and isolate molecules that have therapeutic potential.

“We created a pipeline to harvest the therapeutic potential of the microbiota through specific steps to get to an active molecule,” said Jobin, the Gatorade Distinguished Professor of Medicine in the UF College of Medicine and coleader of the UF Health Cancer Institute’s Immuno-Oncology and Microbiome Research Program.¹

Based on this pipeline, researchers isolated a compound called Bac429 from gut microbes that showed pronounced immunomodulating activities. Bac429 appears to promote antitumor immune responses by boosting immune cell activation in the tumor microenvironment to make it susceptible to immune checkpoint inhibition.²

Preclinical Evidence Shows Significant Tumor Reduction

In mouse models of lung cancer that were highly resistant to immunotherapy, BAC429 showed striking results. When the compound was injected along with the ICIs, there was a significant inhibition of tumor growth compared with immunotherapy alone.

“When we injected Bac429 into the tumors of mice with highly nonresponsive lung cancer, they had 50% less tumor growth after immunotherapy,” Newsome said. “It’s a stark difference.”¹

These results indicate that Bac429 could be used to turn “cold” cancers, which do not respond to immunotherapy, “hot,” or more immunologically active. This strategy would prove especially useful for those currently having limited treatment choices.²

Potential Role in Combination Cancer Therapy

The use of combination therapy has become more prevalent in the treatment of cancer. This is due to the fact that combining drugs that have complementary mechanisms has the potential to increase the efficacy of the treatment without developing resistance. Researchers have found that it may be possible to use the potential of Bac429 together without the need for changing the current treatment approach.

“Combination therapy is being used more and more in cancer,” Jobin said. “One could envision having this molecule attached to an antibody or a lipid nanoparticle like those being pioneered at UF.”¹

Importantly, the researchers emphasized that Bac429 is designed to enhance immune responses without adding invasive procedures or significant toxicity. Newsome noted that the molecule could potentially be administered prior to or concurrently with ICIs to prime the immune system and increase response rates by as much as 50%.¹

Pharmacists’ Implications Moving Forward

Pharmacists are crucial in implementing immunotherapy. This includes medication consultation as well as monitoring any AEs. With more microbiome-based drugs in development, pharmacists will become key players in implementing new approaches involving combination therapies, including biologically active small molecules such as Bac429.

The mechanisms of microbiota-derived therapies will become essential knowledge for pharmacists involved in oncology care. As these microbiota-derived agents progress into clinical trials, pharmacists can provide useful input regarding drug-drug interactions and help patients comprehend the rationale for using combination therapy in immuno-oncologies.³

Although Bac429 is not yet out of the preclinical stage, the data show that the gut microbiome is a powerful modulator of cancer therapy response. Through the use of naturally derived molecules to increase the effectiveness of immunotherapy, there is hope that the role of ICIs will be broadened to a wide range of patients with lung cancers and other diseases.^1,2

REFERENCES

1. Buletti L. Gut bacteria molecule boosts lung cancer treatment response. UF Health News. Published January 5, 2026. Accessed January 12, 2026. https://ufhealth.org/news/2026/gut-bacteria-molecule-boosts-lung-cancer-treatment-response

2. Newsome RC, Liu H, Bright Agbodzi, Gharaibeh RZ, Zhou L, Jobin C. Microbial-derived immunostimulatory small molecule augments anti-PD-1 therapy in lung cancer. Cell Reports Medicine. Published December 19. Accessed January 12, 2026. 2025:102519-102519. doi:10.1016/j.xcrm.2025.102519

3. Kiousi DE, Kouroutzidou AZ, Neanidis K, et al. The Role of the Gut Microbiome in Cancer Immunotherapy: Current Knowledge and Future Directions. Cancers (Basel). 2023;15(7):2101. Published 2023 Mar 31. Accessed January 12, 2026. doi:10.3390/cancers15072101