ACTM-838 - ACTM-838 a novel systemically delivered bacterial immunotherapy that enriches in solid tumors and delivers IL-15/IL-15Rα and STING payloads to engage innate and adaptive immunity in the TME and enable a durable anti-tumor immune response

Sep 28, 2026

STACT is a modular, genetically engineered live attenuated S. Typhimurium platform designed for systemic administration with tissue-specific localization and targeted delivery of large multiplexed payloads. It minimizes systemic toxicity and enriches within the tumor microenvironment (TME) through metabolic dependency, reducing systemic inflammatory cytokines versus the parent strain. ACTM-838 delivers IL-15/IL-15Rα and a constitutively active STING to tumor-resident phagocytic antigen-presenting cells, driving comprehensive TME remodeling and durable anti-tumor immune responses. It decreases exhausted T cells and Tregs while increasing cytolytic T cells and MHCII-high proliferating myeloid cells, upregulates innate/adaptive anti-tumor expression programs, supports T/NK/B infiltration, downregulates DNA damage and TGFβ responses, and shows synergy with anti-PD1 therapy across murine tumor models supported by single-cell RNAseq and flow cytometry.

LanguageEnglish

CategoryStory & Novel

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Abstract

Introduction

[www.oncotarget.com](www.oncotarget.com) Oncotarget, 2025, Vol. 16, pp: 721-740 Research Paper ACTM-838, a novel systemically delivered bacterial immunotherapy that enriches in solid tumors and delivers IL-15/IL-15Rα and STING payloads to engage innate and adaptive immunity in the TME and enable a durable anti-tumor immune response Kyle R. Cron 1, Ping Fang 1, Oanh Pham 1, Julie Janes 1, John Brandenburg 1, William Lu 1, Jonathan Zhu 1, Bret Peterson 1, Sara Tribble 1, Haixing Kehoe 1, Anastasia Makarova 1, Alex Iannello 1, Jean Chan 1, Justin Skoble 1, Hailey He 1, Chris Rae 1, Christopher D . Thanos 1 and Akshata R. Udyavar 1 1Actym Therapeutics, Berkeley, CA 94710, USA Correspondence to: Akshata R. Udyavar, [email](email: akshata.udyavar@pfizer.com)[: akshata.udyavar@pfizer.com](email: akshata.udyavar@pfizer.com)[ ](email: akshata.udyavar@pfizer.com)[Keywords](Keywords: tumor microenvironment)[: tumor microenvironment](Keywords: tumor microenvironment); bacterial vector; myeloid cells; STING; IL-15 Received: February 19, 2025 Accepted: September 25, 2025 Published: October 06, 2025 Copyright: © 2025 Cron et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT STACT is a modular, genetically engineered live attenuated S. Typhimurium bacterial platform that enables tissue-specific localization and cell-targeted delivery of large, multiplexed payloads via systemic administration. It has been engineered to minimize systemic toxicity and to enrich in the tumor microenvironment (TME) via metabolic dependency and showed a decreased systemic inflammatory cytokine profile compared to its parent strain VNP20009 . ACTM-838 utilizes the STACT platform to deliver IL-15/IL15Rα and a constitutively active STING to tumor-resident phagocytic antigen-presenting cells. Upon intravenous (IV) dosing to tumor-bearing mice, ACTM- 838 distributed and enriched in the TME, exhibited specific uptake in tumor-resident phagocytic cells and led to expression of human IL-15/IL15Rα and murine IFNα in the tumor. ACTM-838 induced comprehensive TME changes to an immune permissive anti-tumor phenotype with a decrease in exhausted T-cells and Tregs and an increase in cytolytic T-cells and MHCII-high proliferating myeloid cells. ACTM-838-treated tumors exhibited upregulated anti-tumor innate and adaptive immunity expression profiles, T-, NK-and B-cell infiltration and downregulated cell cycle, DNA damage and TGFβ responses. Single-cell RNAseq and flow cytometry data confirmed activation and infiltration of both innate and adaptive immune cells. ACTM-838 showed durable anti-tumor efficacy in multiple murine tumor models and synergized with anti-PD1 therapy in combination. INTRODUCTION Immune checkpoint blockade (ICB) therapies represent a significant advance in cancer treatment, but only a minority of patients with cancer exhibit durable responses [1] . Rational combinations have boosted responses, but there remains a high unmet need to identify combination therapies that can maximally potentiate an anti-tumor response while minimizing toxicity [2–4] . The effectiveness ofT-cell-targeted ICB relies on the presence of pre-existing anti-tumor T-cells within the TME often referred to as “hot tumors”. Not all patients with high T-cell content, tumor mutation burden or PDL1 expression respond well to ICB, and many patients eventually develop resistance [4, 5] . One mechanism of resistance is the increased infiltration of myeloid and stromal cells leading to secretion of immunosuppressive cytokines and expression of adenosine-generating enzymes and receptors, which promotes tumor progression and T-cell suppression [6] . Thus, it is important to engage andreprogram immunosuppressive innate myeloid cells for antigen presentation and T-cell

FAQs

What is STACT and how does it work in ACTM-838?

STACT is a genetically engineered live attenuated S. Typhimurium platform that supports systemic administration, tissue-specific localization, and cell-targeted delivery. It is engineered to reduce systemic toxicity and enrich in the tumor microenvironment through metabolic dependency.

What payloads does ACTM-838 deliver and to which cells?

ACTM-838 delivers IL-15/IL-15Rα and a constitutively active STING to tumor-resident phagocytic antigen-presenting cells. This enables expression of IL-15/IL-15Rα and interferon responses that engage innate and adaptive immunity.

How does ACTM-838 change the tumor microenvironment and immune responses?

ACTM-838 induces comprehensive TME changes toward an immune-permissive anti-tumor phenotype. It reduces exhausted T cells and Tregs, increases cytolytic T cells and MHCII-high proliferating myeloid cells, boosts innate/adaptive anti-tumor programs, alters cell infiltration patterns, and downregulates cell-cycle, DNA damage, and TGFβ responses.

Sep 28, 2026

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