Harnessing Bacterial Agents to Modulate the Tumor Microenvironment and Enhance Cancer Immunotherapy

Abstract

Cancer immunotherapy has revolutionized cancer treatment by leveraging the immune system to attack tumors. However, its effectiveness is often hindered by the immunosuppressive tumor microenvironment (TME), where a complex interplay of tumor, stromal, and immune cells undermines antitumor responses and allows tumors to evade immune detection. This review explores innovative strategies to modify the TME and enhance immunotherapy outcomes, focusing on the therapeutic potential of engineered bacteria. These bacteria exploit the unique characteristics of the TME, such as abnormal vasculature and immune suppression, to selectively accumulate in tumors. Genetically modified bacteria can deliver therapeutic agents, including immune checkpoint inhibitors and cytokines, directly to tumor sites. This review highlights how bacterial therapeutics can target critical immune cells within the TME, such as myeloid-derived suppressor cells and tumor-associated macrophages, thereby promoting antitumor immunity. The combination of bacterial therapies with immune checkpoint inhibitors or adoptive cell transfer presents a promising strategy to counteract immune suppression. Continued research in this area could position bacterial agents as a powerful new modality to reshape the TME and enhance the efficacy of cancer immunotherapy, particularly for tumors resistant to conventional treatments.

Keywords: antitumor immunity; bacterial therapeutics; cancer immunotherapy; engineered bacteria; immune checkpoint inhibitors; immunosuppression; tumor microenvironment.

Figure 2

Components of the TME. The TME comprises a diverse collection of cancer cells, stromal cells, immune cells, the extracellular matrix (ECM), blood vessels, and various signaling molecules. Cancer-associated fibroblasts (CAFs), adipocytes, and the ECM provide structural support and promote tumor growth. Immune cells, such as tumor-associated macrophages (TAMs), dendritic cells, NK cells, CD8+ T cells, B cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), play complex roles, either supporting or inhibiting tumor progression. Blood vessels within the TME are often abnormal, contributing to hypoxia. Cytokines, chemokines, and growth factors facilitate cell communications, influencing tumor behavior and response to treatment [42]. This intricate interplay within the TME profoundly impacts cancer development, immune evasion, and therapeutic outcomes.

Figure 1

Advancements in bacterial-based therapies for cancer treatment.

Figure 3

CTLA-4 and CD28 interaction with CD80/86. CTLA-4 competes with the costimulatory molecule CD28 for the CD80/86 ligands, where it has a higher affinity and avidity [55,57]. Because CD80 and CD86 both use CD28 to provide a positive costimulatory signal, CTLA-4’s function in competitively inhibiting CD28 is crucial for reducing T cell activation and adjusting the immunological response [57].

Figure 4

Representation of bacteria and bacterial components. Bacterial agents used in cancer therapy are intended to boost the immune system, allowing it to better detect and fight cancer cells. These agents are important in cancer therapy because of their ability to interact with the immune system, disrupt the immunosuppressive tumor microenvironment, and lyse tumor cells, thereby improving the immune response and the efficacy of existing immunotherapies and providing a promising avenue for novel cancer treatments. In recent years, advancements in technology and the attenuation of pathogenic strains have led researchers to concentrate on biochemical and molecular techniques to manipulate bacteria in the fight against cancer. These bacteria can be engineered to selectively target tumors and deliver anticancer medications, proteins, antibodies, enzymes, antigens, and cytokines straight to the cancer cells, thanks to developments in synthetic biology and genetic engineering [87].

Figure 5

The mechanism by which bacteria target tumors. Bacterial toxins and components such as those from Salmonella, Listeria, Clostridium, and Brucella melitensis induce tumor cytotoxicity by triggering autophagy, apoptosis, and immune responses. These bacteria enhance CD8+ T cell activation, reduce regulatory T cells, and promote cytokine production (e.g., IL-1β, TNF-α, IFN-γ), ultimately boosting antitumor immunity through various mechanisms, including gap junction formation, inflammasome activation, and increased neutrophil activity.