The development of cancer vaccines has been intensively pursued over the past 50 years with modest success. However, recent advancements in the fields of genetics, molecular biology, biochemistry, and immunology have renewed interest in these immunotherapies and allowed the development of promising cancer vaccine candidates. Numerous clinical trials testing the response evoked by tumour antigens, differing in origin and nature, have shed light on the desirable target characteristics capable of inducing strong tumour-specific non-toxic responses with increased potential to bring clinical benefit to patients. Novel delivery methods, ranging from a patient’s autologous dendritic cells to liposome nanoparticles, have exponentially increased the abundance and exposure of the antigenic payloads. Furthermore, growing knowledge of the mechanisms by which tumours evade the immune response has led to new approaches to reverse these roadblocks and to re-invigorate previously suppressed anti-tumour surveillance. The use of new drugs in combination with antigen-based therapies is highly targeted and may represent the future of cancer vaccines. In this review, we address the main antigens and delivery methods used to develop cancer vaccines, their clinical outcomes, and the new directions that the vaccine immunotherapy field is taking.

Chemoresistance and limited broad-spectrum efficacy remain major challenges in cancer therapy. The development of agents capable of overcoming resistance and exhibiting activity across diverse tumour types is therefore critical to improving treatment outcomes. Here, we demonstrate the antiproliferative activity of a steroidal-nitroxide hybrid across multiple cell lines. CS187, a first-generation hybrid identified from previous work in cervical cancer, exhibited concentration-dependent antiproliferative activity with associated morphological changes in prostate (C4-2B), breast (MCF-7), and lung cancer (H460 and A549) cells at concentrations of 11-50 µM. In-combination with cisplatin, CS187 potentiated antiproliferative effects, achieving comparable growth inhibition at reduced cisplatin doses. Assessment of reactive oxygen species (ROS) levels revealed that CS187, both alone and in-combination with cisplatin, induced sustained intracellular oxidative stress, whereas cisplatin monotherapy exhibited attenuation over the time course. Together, these findings suggest that CS187 acts predominantly through a cytostatic mechanism and may interfere with redox-mediated adaptive responses that typically limit cisplatin efficacy. This work identifies CS187 as a promising redox-modulating scaffold capable of enhancing chemotherapeutic efficacy while potentially enabling dose reduction across multiple cancer types.

Inflammation and redox imbalance are hallmarks of many diseases. Here, we report the synthesis and systematic evaluation of steroid-nitroxide hybrid compounds as dual-acting anti-inflammatory and redox-modulating agents. Hybrids were generated via ester (1a-c, 2a-b), amide (1d-h), and ether (3a-c) linkages at the C21 position of corticosteroids prednisolone, cortisol, and dexamethasone. The hybrids exhibit glucocorticoid receptor (GR) activity and suppress IL-6 secretion in vitro at variable potencies, some comparable to commercial corticosteroids. Cellular metabolic evaluation demonstrates various rates of intracellular cleavage for ester- and amide-linked hybrids, while ether-linked hybrids remain intact. Assessment of general reactive oxygen species (ROS) levels via the fluorogenic probe 2',7'-dichlorofluorescein diacetate (DCFDA) demonstrated linker-dependent pro-oxidative effects, with poorly labile and non-cleavable compounds (1a, 3a-c) causing sustained ROS elevation, while cleavable hybrids produced only transient, recoverable increases. Notably, one hybrid (1a) demonstrated higher ROS elevation in A549 cells over normal human fibroblasts (i.e. NFF cells) suggesting certain structural features of this hybrid induce specificity. Live-cell imaging using fluorescent analogues supports the mechanism of intracellular cleavage and efflux for cleavable hybrids, while non-cleavable hybrids remain within the cell. These findings demonstrate that steroidal-nitroxide hybrids harness both anti-inflammatory and redox modulation pathways, positioning them as a novel treatment strategy where dual anti-inflammatory and pro-oxidant strategies are advantageous.

From the initial discovery of FK506 binding protein 12 (FKBP12), the FKBP familial group of proteins have since been identified to be highly conserved proteins within eukaryotes. As functional proteins, the isoforms of FKBPs display a myriad of functions within the systemic environment. FKBP proteins are known to possess roles in apoptosis, cancer, cardiac support, cell development, neuronal function, protein folding and trafficking, cell receptor signalling and transcriptional control, whilst conserved across multiple types of tissues and subcellular components. Of the 16 member FKBP family, FKBP51 and FKBP52 are the only members that exhibit a diverse role in the regulation of steroid hormone receptors. Beyond their involvement in receptor signalling, binding and nuclear translocation, studies have implicated FKBP51 and FKBP52 in the pathogenesis of a variety of hormone dependent diseases and cancers. Furthermore, selective inhibition of FKBP51 has advanced considerably, whereas FKBP52 selectivity remains an ongoing challenge. This review summarises the current mechanistic understanding of the FKBP protein family, with a focus on the roles of FKBP51 and FKBP52 in steroid hormone-driven cancers, highlighting key knowledge gaps, translational biomarkers, pre-clinical efforts and clinical progress.