Expert Reviews in Molecular Medicine

Adenosinergic Signalling in Cervical Cancer Microenvironment

Abstract Despite the emergence of the first human papillomavirus vaccine, the incidence of cervical cancer is still responsible for more than 350,000 deaths yearly. Over the past decade, ecto-5′-nucleotidase (CD73/5′-NT) and extracellular adenosine (ADO) signalling has been the subject of many investigations to target cancer progression. In general, the adenosinergic axis has been linked to tumourigenic effects. However, CD73 can play contradictory effects, probably dependent on the tumour type, tumour microenvironment and tumour stage, thus being in some circumstances, inversely related to tumour progression. We herein reviewed the pathophysiological function of CD73 in cervical cancer and performed in silico analysis of the main components of the adenosinergic signalling in human tissues of cervical cancer compared to non-tumour cervix tissue. Our data showed that the NT5E gene, that encoded CD73, is hypermethylated, leading to a decreased CD73 expression in cervical cancer cells compared to normal cells. Consequently, the high availability of ADO cytoplasmatic/extracellular leads to its conversion to AMP by ADK, culminating in global hypermethylation. Therefore, epigenetic modulation may reveal a new role for CD73 in cervical cancer.

Microbiome-driven resistance in cervical cancer therapy: from mechanistic dissection to clinical translation

Abstract Cervical cancer remains a major global health burden. Despite standard-of-care therapies, 30–50% of locally advanced-stage patients develop treatment resistance, leading to recurrence and mortality. While tumour-intrinsic mechanisms (e.g., DNA methylation, cancer-associated fibroblasts) explain only partial resistance heterogeneity, emerging evidence identifies the microbiome as a critical modulator of therapeutic efficacy. This review synthesizes recent advances demonstrating that vaginal microbial dysbiosis, characterized by Lactobacillus iners enrichment and L. crispatus depletion, drives resistance through lactate-mediated metabolic rewiring, immune checkpoint stabilization and drug metabolism alteration. Longitudinal studies reveal dynamic microbiome trajectories during therapy, with geographic variations (notably HIV co-infection in sub-Saharan Africa) further modulating treatment responses. We critically evaluate microbiome-based interventions, from probiotics to engineered bacteria, including synthetic biology-driven precision microbiome therapies, and establishing standardized multi-centre trial protocols. Bridging mechanistic insights with clinical application represents a paradigm shift towards microbiome-informed cervical cancer management.

PARP enzymes and mono-ADP-ribosylation: advancing the connection from interferon-signalling to cancer biology

Abstract ADP-ribosyltransferases of the PARP family encompass a group of enzymes with variegated regulatory functions in cells, ranging from DNA damage repair to the control of cell-cycle progression and immune response. Over the years, this knowledge has led to the use of PARP1/2 inhibitors as mainstay pharmaceutical strategies for the treatment of ovarian, pancreatic, prostate and breast cancers, holding mutations in genes encoding for proteins involved in the DNA repair mechanisms (synthetic lethality). Meanwhile, the last decade has witnessed significant progress in comprehending cellular pathways regulated by mono-ADP-ribosylation, with a huge effort in the development of novel selective compounds to inhibit those PARPs endowed with mono-ADP-ribosylation activity. This review focuses on the progress achieved in the cancer field, delving into most recent findings regarding the role of a subset of enzymes – the interferon-stimulated PARPs – in cancer progression.

Efficacy of immune checkpoint inhibitor monotherapy or combined with other small molecule-targeted agents in ovarian cancer

Abstract Ovarian cancer is the most lethal female reproductive system tumour. Despite the great advances in surgery and systemic chemotherapy over the past two decades, almost all patients in stages III and IV relapse and develop resistance to chemotherapy after first-line treatment. Ovarian cancer has an extraordinarily complex immunosuppressive tumour microenvironment in which immune checkpoints negatively regulate T cells activation and weaken antitumour immune responses by delivering immunosuppressive signals. Therefore, inhibition of immune checkpoints can break down the state of immunosuppression. Indeed, Immune checkpoint inhibitors (ICIs) have revolutionised the therapeutic landscape of many solid tumours. However, ICIs have yielded modest benefits in ovarian cancer. Therefore, a more comprehensive understanding of the mechanistic basis of the immune checkpoints is needed to improve the efficacy of ICIs in ovarian cancer. In this review, we systematically introduce the mechanisms and expression of immune checkpoints in ovarian cancer. Moreover, this review summarises recent updates regarding ICI monotherapy or combined with other small-molecule-targeted agents in ovarian cancer.