Isaac Montgomery

Background: Cancer is a group of related diseases characterized by malignant hyperplasia and metastasis that can originate from many cells in the body (1). It represents the second leading cause of death in the United States (2) with a projected burden of over 2 million new cases and 600,000 deaths in 2025 (3). One hallmark of cancer is its ability to evade immune recognition and elimination (4). Recent research has focused on using bacteria to stimulate the immune system to target cancer (5), called bacterial-based cancer therapy (BBCT). The first defenders against bacteria are neutrophils, the most abundant white blood cell in the body (6). Although neutrophils are increasingly recognized for their anticancer potential (7), information about how neutrophils facilitate response to BBCT is sparse.

Research Question: How do neutrophils and bacterial therapies work together to produce antitumor immunity?

Methods: a literature review was conducted using PubMed and Google Scholar to find papers relating cancer, bacterial therapy, and neutrophils. Key search terms include bacterial anticancer therapy, neutrophils,

Results: In a study done by Yam et al (8), injection of Staphylococcys aureus bioparticles into lung carcinoma, melanoma, breast cancer, and pancreatic ductal adenocarcinoma tumors in mice increased neutrophil infiltration into the tumor, as well as macrophages, T cells and dendritic cells. The proportion of neutrophils increased, while the proportion of other cells did not change. S. aureus treated neutrophils had increased expression of iNOS and CD11b, which are a neutrophilic antimicrobial defense and activation marker, respectively. This therapy decreased growth of all four tumor types reported. This effect is dependent on neutrophils, evidenced by reversal upon administration of anti-Ly6G antibodies to deplete neutrophils.  Shinnoh et al (9) demonstrated that in culture, Clostridium butyricum induces human neutrophils to release tumor necrosis factor-related apoptosis inducing ligand (TRAIL), an apoptotic cytokine. The supernatant of C. butyricum-treated neutrophils was sufficient to induce apoptosis in human bladder cancer cultures, but blocking the TRAIL receptor DR5 on the tumor cells significantly reduced the apoptotic induction of the supernatant, indicating that the effects are at least partly mediated by TRAIL. Similarly, intratumoral injection of C. butyricum significantly delayed tumor growth.

Conclusions: Despite interest in neutrophils and bacterial therapy in a cancer context, information on the cross between them is rare. The few papers that have investigated this interaction have concluded that neutrophils are vital to the success of various bacterial anticancer therapies. Importantly, there’s little or no information comparing how different bacterial species or products differentially activate neutrophils. Papers use C. butyricum, S. aureus, S. enterica, L. monocytogenes, and other bacterial species without directly comparing them. The same is true of using different cancer models: the literature is filled with lung cancer, pancreatic cancer, colon cancer and more, but comparing between different cancer types is difficult to find. Understanding these research gaps will allow investigators to fill them more easily, potentially improving patient outcomes.

Work Cited:

1. What Is Cancer? Updated 2021. Accessed February 20, 2025. https://www.cancer.gov/about-cancer/understanding/what-is-cancer
2. Mortality in the United States, 2022. NCHS Data Brief. 2024;492. https://www.cdc.gov/nchs/products/databriefs/db492.htm
3. Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10-45. doi:3322/caac.21871
4. Roerden M, Spranger S. Cancer immune evasion, immunoediting and intratumour heterogeneity. Nat Rev Immunol. Published online January 2, 2025:1-17.
5. Tang Q, Peng X, Xu B, Zhou X, Chen J, Cheng L. Current Status and Future Directions of Bacteria-Based Immunotherapy. Front Immunol. 2022;13. doi:3389/fimmu.2022.911783
6. Treffers LW, Hiemstra IH, Kuijpers TW, van den Berg TK, Matlung HL. Neutrophils in cancer. Immunological Reviews. 2016;273(1):312-328. doi:1111/imr.12444
7. Ohms M, Möller S, Laskay T. An Attempt to Polarize Human Neutrophils Toward N1 and N2 Phenotypes in vitro. Front Immunol. 2020;11.
8. Yam AO, Bailey J, Lin F, et al. Neutrophil Conversion to a Tumor-Killing Phenotype Underpins Effective Microbial Therapy. Cancer Research. 2023;83(8):1315-1328. doi:10.1158/0008-5472.CAN-21-4025
9. et al. Clostridium butyricum MIYAIRI 588 shows antitumor effects by enhancing the release of TRAIL from neutrophils through MMP-8. International Journal of Oncology. 2013;42(3):903-911. doi:10.3892/ijo.2013.1790