Tito A. Sandoval

Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer

Abstract Iron accumulation in tumors contributes to disease progression and chemoresistance. Although targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells toward an immunostimulatory state characterized by the production of type-I IFN and overexpression of molecules that activate NK cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type-I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T-cell–centric modalities. Significance: This study uncovers that targeting dysregulated iron accumulation in ovarian tumors represents a major therapeutic opportunity. Iron chelation therapy using an FDA-approved agent causes immunogenic stress responses in ovarian cancer cells that delay metastatic disease progression and enhance the effects of first-line chemotherapy. See related commentary by Bell and Zou, p. 1771

Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer

Abstract Lysophosphatidic acid (LPA) is a bioactive lipid enriched in the tumor microenvironment of immunosuppressive malignancies such as ovarian cancer. Although LPA enhances the tumorigenic attributes of cancer cells, the immunomodulatory activity of this phospholipid messenger remains largely unexplored. Here, we report that LPA operates as a negative regulator of type I interferon (IFN) responses in ovarian cancer. Ablation of the LPA-generating enzyme autotaxin (ATX) in ovarian cancer cells reprogrammed the tumor immune microenvironment, extended host survival, and improved the effects of therapies that elicit protective responses driven by type I IFN. Mechanistically, LPA sensing by dendritic cells triggered PGE2 biosynthesis that suppressed type I IFN signaling via autocrine EP4 engagement. Moreover, we identified an LPA-controlled, immune-derived gene signature associated with poor responses to combined PARP inhibition and PD-1 blockade in patients with ovarian cancer. Controlling LPA production or sensing in tumors may therefore be useful to improve cancer immunotherapies that rely on robust induction of type I IFN. Significance: This study uncovers that ATX–LPA is a central immunosuppressive pathway in the ovarian tumor microenvironment. Ablating this axis sensitizes ovarian cancer hosts to various immunotherapies by unleashing protective type I IFN responses. Understanding the immunoregulatory programs induced by LPA could lead to new biomarkers predicting resistance to immunotherapy in patients with cancer. See related commentary by Conejo-Garcia and Curiel, p. 1841. This article is highlighted in the In This Issue feature, p. 1825

Transgelin 2 guards T cell lipid metabolism and antitumour function

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids

Chemoradiation Reprograms Tumor Cells and the Immune Microenvironment in Cervical Cancer

Abstract Despite advances in screening and prevention, cervical cancer remains a leading cause of cancer-related deaths worldwide, underscoring the need for better treatments. In this study, we conducted a multicohort longitudinal study of human cervical tumors and the tumor microenvironment during chemoradiotherapy (CRT) and integrated RNA sequencing and single-cell transcriptomics to define the cellular and molecular programs shaping cell interactions and how CRT alters them. The analysis identified multiple therapeutic targets in CRT-resistant tumors, notably including MDM2, a key mediator of radiation responses in tumor and immune cells. MDM2 inhibition enhanced the effects of radiotherapy in human papillomavirus (HPV)–positive, TP53 wild-type cervical cancer cells; improved radiation response; and reshaped the immune landscape in preclinical models. These findings highlight the potential of combining MDM2 inhibition with CRT to overcome resistance and improve patient outcomes. The insights into therapy-induced changes in tumor and immune compartments could guide improved strategies against treatment-resistant HPV-positive cancers. Significance: Mapping of the impact of chemoradiation on cellular interactions in cervical cancer reveals how treatment reshapes the tumor microenvironment and highlights targets for developing future immunotherapeutic approaches. See related commentary by Klopp, p. 1540