The promise of synthetic bacteria in cancer immunotherapy: Revitalizing tumor immunity via IL-10R modulation

The immune system is the body's main cancer surveillance system. Unlike surgery, radiation, and chemotherapy, which are typically nonspecific, cancer immunotherapy holds tremendous promise as it harnesses the high specificity of a person's immune system to kill cancer cells selectively. This promising approach includes checkpoint inhibitors, chimeric antigen receptor (CAR)-T cell therapy, cancer vaccines, cytokines, and monoclonal antibodies, among others. Cancer immunotherapy has progressed tremendously, resulting from basic science discoveries in the molecular and cellular biology of T cells. Various immune system components protect the host against tumor development and escape, and immune checkpoints tightly regulate these. Inhibitory immune checkpoint inhibitors, such as those against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), have been shown to enhance the body's immune response against cancer [1]. Engineering T cells to express CARs to recognize specific tumor antigens triggers the destruction of cancer cells. In this commentary, we want to highlight the recent work by Yichuan Xiao, Chenli Liu, and coworkers on engineered bacteria for cancer immunotherapy [2] and share our perspectives on the future of bacterial immunotherapy.

ENGINEERED TUMOR-KILLING BACTERIA

In recent years, microbial-based cancer therapy has emerged as a promising avenue, leveraging the inherent tropism of certain bacteria toward solid tumors [[3], [4], [5]]. This approach traces its roots to historical observations of cancer remission following bacterial infections, dating back nearly two centuries [6]. Early investigations identified bacterial genera such as Escherichia, Salmonella, Listeria, Clostridium, and Bifidobacterium, which preferentially colonize hypoxic tumor regions [6]. Despite early promise, the translation of microbial therapy into effective clinical interventions has encountered hurdles, primarily stemming from challenges in achieving sustained and localized delivery of therapeutic payloads within the tumor microenvironment (TME). Additionally, safety concerns related to potential infections and off-target effects pose significant obstacles. While the activation of anti-tumor immunity of tumor-killing bacteria has long been recognized, how bacteria evade antimicrobial immune defenses, a dichotomy of seemingly contradictory immune responses, has remained a challenge to be overcome.

LEVERAGING IL-10/IL-10R SIGNALING IN BACTERIAL IMMUNOTHERAPY

The study by Yichuan Xiao, Chenli Liu, and colleagues reveals a novel bacterial immunotherapy strategy that exploits the hysteresis of interleukin-10 (IL-10)/IL-10 receptor (IL-10R) signaling to evade phagocytic clearance while reprogramming the TME [2] (Figure 1). This duality is achieved through a finely tuned burst of IL-10, which dampens the innate clearance of the bacteria while enhancing adaptive anti-tumor immunity. The study demonstrated that engineered Salmonella enterica exploits this mechanism to drive immune cells within the tumor into a tumor-specific IL-10R^hi state. This enables the bacteria to simultaneously evade neutrophil-mediated clearance and promote IL-10-producing macrophages that support the expansion and reactivation of exhausted CD8⁺ T cells. The approach led to complete tumor regression, protection from recurrence, and suppression of metastasis across multiple tumor models. Intriguingly, analysis of human tumors revealed a conserved IL-10R^hi signature, suggesting this mechanism may be broadly applicable across cancer types. Notably, IL-10 has been shown to reverse T cell exhaustion and restore effector function in tumor-infiltrating lymphocytes, a key barrier to durable immunotherapy responses [7]. Moreover, IL-10 delivery has been reported to enhance the proliferation, survival, and cytotoxic activity of CAR-T cells in solid tumors [8]. Together, these findings suggest that the spatial and temporal induction of IL-10 in the TME may be a powerful strategy not only to evade immune clearance of engineered bacteria but also to potentiate T cell-based therapies through targeted rejuvenation of dysfunctional T cells.

Figure 1.

IL-10 differentiation in tumoral tissues

Depiction of the dual function of IL-10 mediated by engineered Salmonella for cancer immunotherapy. Abbreviations: TLR4, toll-like receptor 4; IL-10, interleukin-10; IL-10R, IL-10 receptor.

FUTURE DIRECTION

The discovery reported by Yichuan Xiao and Chenli Liu ushered in a new paradigm in bacterial immunotherapy, where an engineered bacterial strain can evade antimicrobial immune defenses while promoting anti-tumor activity via IL-10/IL-10R signaling. Despite these promising advances, important translational challenges remain. A key consideration is the route of bacterial delivery. While intravenous injection allows systemic tumor access, especially for metastatic or inaccessible lesions, its clinical utility is limited by human sensitivity to bacterial endotoxins [9], which drastically reduces the maximum tolerated dose. While preclinical mouse models had shown promising tumor colonization and regression, the clinical results in humans were markedly less encouraging. Notably, a landmark Phase I clinical trial investigated the intravenous administration of an attenuated Salmonella typhimurium strain (VNP20009) in patients with metastatic melanoma [10]. Only one of six patients receiving the maximum tolerated dose showed any evidence of bacterial colonization in the tumor. Moreover, dose escalation was limited by toxicity, and no objective tumor regressions were observed. This underscores the need for next-generation microbial platforms with reduced toxicity and enhanced tumor-targeting capacity. Moving forward, three pressing questions merit exploration. Can we incorporate genetic circuits to sense and respond to tumor-specific cues such as elevated lactic acid, a hallmark of over 90% of solid tumors? Can these engineered bacteria be validated in physiologically relevant human tissue models, in alignment with recent initiatives to promote human-based research and reduce reliance on animal models? Can the microbial systems provide added benefits in conjunction with existing cancer immunotherapies? Addressing these questions will be critical for translating microbial immunotherapies into clinically viable treatments.

AUTHOR CONTRIBUTIONS

Jiahe Li: writing – original draft, writing – review & editing. Allen P. Liu: conceptualization, writing – original draft, writing – review & editing.

Declaration of competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.