Modulating immune responses by targeting DNA repair and metabolism

<jats:p>&lt;p dir="ltr"&gt;Immune responses must be tightly controlled to protect the host while avoiding pathological inflammation. In cancer, insufficient immune activation and T-cell exhaustion allow malignant cells to escape immune surveillance, whereas in autoimmune diseases, excessive or sustained T-cell activation drives chronic tissue damage. Although immune checkpoint blockade and anti-inflammatory therapies have transformed treatment strategies, many patients show inadequate responses or develop treatment resistance. This highlights the need to identify upstream cellular processes that regulate immune states across disease contexts.&lt;/p&gt;&lt;p dir="ltr"&gt;DNA repair and one-carbon metabolism are essential for cell survival and proliferation, but they also shape inflammatory signalling and immune-cell function. This thesis investigates whether pharmacological targeting of DNA repair-associated pathways and one-carbon metabolism can be used to modulate immune responses in cancer and autoimmune disease.&lt;/p&gt;&lt;p dir="ltr"&gt;In Paper I, we investigated the mitotic MTH1 inhibitor TH1579 as a modulator of tumour immunogenicity. TH1579 induced PD-L1 expression and increased inflammatory mediators including IFN-B, CCL5 and CXCL10 through activation of the cGAS-STING pathway. In a syngeneic tumour model, TH1579 enhanced the anti-tumour effect of PD-L1 blockade, suggesting that targeting DNA damage- associated processes can promote a more immune-responsive tumour microenvironment.&lt;/p&gt;&lt;p dir="ltr"&gt;In Paper II, we examined MTHFD2-dependent one-carbon metabolism in rheumatoid arthritis as a model of T-cell-driven autoimmunity. We identified an NFATc1-regulated MTHFD2 axis in pathogenic T cells and showed that pharmacological inhibition of MTHFD1/2 with TH9619 reduced NF-KB-associated inflammatory programmes in vitro. In vivo, TH9619 suppressed proinflammatory cytokine production, increased the frequency of regulatory T cells and protected against joint inflammation.&lt;/p&gt;&lt;p dir="ltr"&gt;In Paper III, we extended the concept of metabolic immunomodulation to cancer and demonstrated that the anti-tumour efficacy of TH9619 was dependent on CD8+ T cells. MTHFD1/2 inhibition increased formate availability and chemokine expression in tumour cells, which were associated with enhanced CD8+ T-cell activity and infiltration, respectively. These findings show that targeting one-carbon metabolism in tumour cells can promote CD8+ T-cell-mediated anti- tumour responses and contribute to tumour suppression.&lt;/p&gt;&lt;p dir="ltr"&gt;Together, these studies demonstrate that DNA damage-associated processes and one-carbon metabolism act as immunological regulators and remodel immune responses. Targeting these processes can enhance anti-tumour immunity or suppress pathogenic autoimmune inflammation, depending on the biological context. This thesis therefore supports DNA repair and metabolism as therapeutic entry points for modulating immune responses in cancer and autoimmune disease.&lt;/p&gt;&lt;h3 dir="ltr"&gt;List of scientific papers&lt;/h3&gt;&lt;p dir="ltr"&gt;I. &lt;b&gt;Shen, J.&lt;/b&gt;, Guillén Mancina, E., Chen, S., Manolakou, T., Gad, H., Warpman Berglund, U., Sanjiv, K., Helleday, T. Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway. Oncogenesis 13, 17 (2024). &lt;a href="https://doi.org/10.1038/s41389-024-00518-1" target="_blank" rel="noreferrer"&gt;https://doi.org/10.1038/s41389-024-00518-1&lt;/a&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;II. Manolakou, T., &lt;b&gt;Shen, J.&lt;/b&gt;, Boddul, S., Samiotaki, M., Panagias, M. A., Sentis, G., Silva, T. A., Argyriou, A., Nikolopoulos, D., Sanjiv, K., Chemin, K., Wermeling, F., Henriksson, M., Slipicevic, A., Jakobsson, P .- J., Chatzidionysiou, K., Helleday, T. Targeting NFATc1-regulated MTHFD2 one-carbon metabolism to suppress sustained T cell-mediated inflammation in rheumatoid arthritis. Sig Transduct Target Ther 11, 226 (2026). &lt;a href="https://doi.org/10.1038/s41392-026-02752-y" target="_blank" rel="noreferrer"&gt;https://doi.org/10.1038/s41392-026-02752-y&lt;/a&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;III. &lt;b&gt;Shen, J.&lt;/b&gt;, Shi, W., Mazza, E., Agrò, S. N., Stigsdotter, H., Lingstaedt, M., Sanjiv, K., Chalkiadaki, C., Panagias, M. A., Qin, Z., Xi, P., Pham, T., Chatzidionysiou, K., Henriksson, M., Slipicevic, A., Lugli, E., Manolakou, T., Helleday, T. MTHFD1/2 inhibition couples replication stress to immune activation in non-small cell lung cancer. [Manuscript]&lt;/p&gt;</jats:p>