Immune checkpoint blockade with antibodies against PD-1 and PD-L1 has become one of the most successful approaches in oncology. However, some patients fail to respond or develop resistance over time. The IFN-γ signaling pathway plays a central role in treatment efficacy by boosting antigen presentation through MHC-I molecules. At the same time, IFN-γ also stimulates PD-L1 expression, which can lead to T-cell exhaustion and acquired resistance.
Acquired resistance is often associated with mutations in the IFN-γ signaling pathway (JAK1/2) or antigen presentation machinery. These mutations prevent tumor cells from upregulating MHC-I in response to IFN-γ, resulting in T-cell inactivation and loss of PD-1 blockade efficacy. Interestingly, loss-of-function IFN-γ pathway mutations in tumor cells can also facilitate tumor clearance by activating other immune branches, including CD4+ T cells, NK cells, and myeloid cells. This provides a rationale for combining PD-1 blockade with IFN-γ therapy.
However, systemic IFN-γ treatment is limited by severe toxicities. A potential solution is localized delivery of IFN-γ directly into tumors.
The Columbia University team designed the SLIC-IFN-γ strain, a probiotic bacterium that selectively proliferates inside tumors and secretes interferon-γ.
In mouse models, SLIC-IFN-γ showed robust anti-tumor activity both as a monotherapy and in combination with PD-1 blockade. Tumor-secreted IFN-γ enhanced the activation of antigen-specific CD4+ and CD8+ T cells, helping to overcome primary resistance to PD-1 therapy. In addition, IFN-γ stimulated NK cells, allowing tumors to bypass mechanisms of acquired resistance.
A single intravenous injection of SLIC-IFN-γ led to IFN-γ release only within tumor tissues, where bacteria proliferated. This approach prevented systemic toxicities such as flu-like symptoms and hematological side effects. Alongside bacterial adjuvant effects, SLIC-IFN-γ activated myeloid cells (macrophages, cDC1) in the tumor microenvironment and regional lymph nodes, while also triggering systemic anti-tumor immunity in distant untreated tumors.
Chronic IFN-γ exposure can upregulate PD-L1, causing T-cell exhaustion and resistance. In mouse and cell models, SLIC-IFN-γ indeed increased PD-L1 expression, but when combined with PD-1 blockade, this became a therapeutic advantage: the combination rendered even intrinsically resistant tumors more responsive to immunotherapy.
Bacterially delivered IFN-γ monotherapy was also effective in models of acquired resistance. In tumors with MHC-I defects or IFN-γ signaling deficiencies, this therapy activated NK cells and produced anti-tumor responses. Combining SLIC-IFN-γ with PD-1 blockade significantly improved survival, particularly in models where PD-1 blockade alone had minimal effect.
Researchers propose several strategies for further development of SLIC-IFN-γ:
- Increasing IFN-γ dosage through bacterial engineering
- Using IFN-γ variants that upregulate MHC-I without inducing PD-L1 expression
- Creating combined bacterial strains that secrete additional immunotherapeutic molecules
Conclusion
The tumor-targeted delivery of interferon-γ via probiotic bacteria SLIC-IFN-γ demonstrates safety, versatility, and efficacy. Intravenous SLIC-IFN-γ therapy significantly reduced tumor progression and improved survival without systemic toxicity. This approach holds promise for clinical application in combination with PD-1 blockade, offering a way to overcome both primary and acquired resistance to cancer immunotherapy.
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