951 Engineered tumor-homing bacteria enable systemic combination immune checkpoint blockade and cytokine immunotherapy
Year: 2026
Type: conference-paper
Abstract: Background Immune checkpoint blockade (ICB) has transformed cancer treatment but remains ineffective for many patients because of limited intratumoral drug delivery, systemic toxicity, and an immunosuppressive tumor microenvironment. Engineered bacteria have recently emerged as programmable therapeutic platforms capable of selectively colonizing tumors following systemic administration and delivering immunomodulatory payloads to enhance antitumor immunity. 1 2 Here, we developed a modular bacterial surface-display platform for the systemic delivery of immune checkpoint nanobodies and cytokine stimulation to improve cancer immunotherapy.Methods We engineered Escherichia coli to display anti-CTLA-4 and anti-PD-L1 nanobodies using five bacterial outer membrane protein scaffolds. Functional target binding and antitumor efficacy were compared to identify the optimal surface-display platform. The optimized checkpoint nanobody-displaying strain was combined with a second engineered strain displaying membrane-anchored decoy-resistant IL-18 (mDR18). Therapeutic efficacy was evaluated following intratumoral and intravenous administration in multiple syngeneic murine tumor models. Tumor growth, survival, immune memory, biodistribution, systemic cytokine responses, and immune remodeling were assessed using flow cytometry and multiplex cytokine profiling.Results Among the five bacterial surface-display scaffolds evaluated, YiaT181 mediated the most efficient functional nanobody presentation and superior antitumor activity. Intratumoral administration significantly suppressed MC38 tumor growth compared with alternative display scaffolds. Following intravenous administration, combination therapy consisting of YiaT181-displayed checkpoint nanobodies and OmpA-displayed mDR18 achieved significantly greater tumor control and prolonged survival than either monotherapy or conventional anti-CTLA-4 plus anti-PD-L1 antibody therapy in the Yummer1.7 melanoma model. Complete tumor regression occurred in a subset of treated mice, which rejected subsequent tumor rechallenge, demonstrating durable antitumor immune memory ( figure 1). Immune profiling revealed enhanced intratumoral CD8+ T-cell infiltration, reduced regulatory T-cell abundance, and remodeling of the tumor immune microenvironment toward a pro-inflammatory state (figure 2). Biodistribution studies demonstrated preferential tumor accumulation with minimal systemic toxicity following intravenous administration.Conclusions This study establishes engineered bacterial surface display as a versatile off-the-shelf immunotherapy platform capable of systemically delivering combination immune checkpoint blockade and cytokine stimulation. This modular platform substantially enhances antitumor immunity, outperforms conventional checkpoint antibody therapy in multiple preclinical tumor models, and provides a broadly applicable platform for next-generation engineered microbial cancer immunotherapies.References Yang S, Sheffer M, Kaplan I, Wang Z, et al. Non-pathogenic Escherichia coli displaying decoy-resistant IL18 mutein boosts anti-tumor and CAR NK cell responses. Nat Biotechnol. 2024.Chowdhury S, Castro S, Coker C, et al. Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nat Med. 2019;25:1057-1063.Abstract 951 Figure 1Intravenous engineered bacterial immunotherapy outperforms conventional immune checkpoint blockade and prolongs survival. Systemic engineered bacterial combination therapy suppresses tumor growth, prolongs survival, and induces durable antitumor immune memory in the Yummer1.7 melanoma modelAbstract 951 Figure 2Systemic engineered bacteria preferentially accumulate in tumors and remodel the tumor immune microenvironment. Systemically administered engineered bacteria preferentially accumulate in tumors and promote antitumor immune remodeling following intravenous treatment
Authors: Zongqi Wang, Jiahe Li
Institution: University of Michigan
Language: English
Topic: Bacterial Cancer Therapy
Subfield: Biotechnology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225189367