Cancer vaccines are increasingly being studied as a possible strategy to prevent and treat cancers. While several prophylactic vaccines for virus-caused cancers are approved and efficiently used worldwide, the development of therapeutic cancer vaccines needs to be further implemented. Virus-like particles (VLPs) are self-assembled protein structures that mimic native viruses or bacteriophages but lack the replicative material. VLP platforms are designed to display single or multiple antigens with a high-density pattern, which can trigger both cellular and humoral responses. The aim of this review is to provide a comprehensive overview of preventive VLP-based vaccines currently approved worldwide against HBV and HPV infections or under evaluation to prevent virus-caused cancers. Furthermore, preclinical and early clinical data on prophylactic and therapeutic VLP-based cancer vaccines were summarized with a focus on HER-2-positive breast cancer.

Immune checkpoint inhibitors (ICIs) improve the survival of patients with multiple types of cancer. However, low response rates and atypical responses limit their success in clinical applications. The paradoxical acceleration of tumor growth after treatment, defined as hyperprogressive disease (HPD), is the most difficult problem facing clinicians and patients alike. The mechanisms that underlie hyperprogression (HP) are still unclear and controversial, although different factors are associated with the phenomenon. In this review, we propose two factors that have not yet been demonstrated to be directly associated with HP, but upon which it is important to focus attention. IFN-γ is a key cytokine in antitumor response and its levels increase during ICI therapy, whereas CD38 is an alternative immune checkpoint that is involved in immunosuppressive responses. As both factors are associated with resistance to ICI therapy, we have discussed their possible involvement in HPD with the conclusion that IFN-γ may contribute to HP onset through the activation of the inflammasome pathway, immunosuppressive enzyme IDO1 and activation-induced cell death (AICD) in effector T cells, while the role of CD38 in HP may be associated with the activation of adenosine receptors, hypoxia pathways and AICD-dependent T-cell depletion.

Chondrosarcoma (CS), the second most common malignant bone tumor after osteosarcoma, accounts for 20–30% of all malignant bone tumors. It mainly affects adults, middle-aged, and elderly people. The CS family includes various entities displaying peculiar biological, genetic, and epigenetic characteristics and clinical behaviors. Conventional CS is the most common subtype. High-grade, dedifferentiated, and mesenchymal CS, as well as unresectable and metastatic CS, exhibit poor prognoses due to their intrinsic resistance to radiotherapy and chemotherapy, underscoring the urgent need for novel therapeutic strategies. CS research is dealing with several challenges. Experimental studies can rely on animal and patient-derived models, but the paucity of representative near-patient preclinical models has hampered predictive drug screening research. This review describes the main clinical and molecular features of CS subtypes, discussing recent data on the genetic alterations and molecular mechanisms involved in CS pathogenesis and progression. The review provides an overview of the current in vitro and in vivo CS models, discusses their advantages and limitations, and highlights the recent efforts in the development of new targeted therapies against CS dependencies, including IDH1/2 mutations, NAD⁺ dependency, and SIRT1-HIF-2α axis, or exploring DR5 targeting, antiangiogenic therapies, epigenetic drugs, and immunological approaches. All such strategies, in combination with advanced preclinical modeling and personalized multi-omic profiling, hold promise for improving the survival of patients with advanced CS.

Synovial sarcomas (SyS) are rare malignant tumors predominantly affecting children, adolescents, and young adults. The genetic hallmark of SyS is the t(X;18) translocation encoding the SS18-SSX fusion gene. The fusion protein interacts with both the BAF enhancer and polycomb repressor complexes, and either activates or represses target gene transcription, resulting in genome-wide epigenetic perturbations and altered gene expression. Several experimental in in vivo models, including conditional transgenic mouse models expressing the SS18-SSX fusion protein and spontaneously developing SyS, are available. In addition, patient-derived xenografts have been estab-lished in immunodeficient mice, faithfully reproducing the complex clinical heterogeneity. This review focuses on the main molecular features of SyS and the related preclinical in vivo and in vitro models. We will analyze the different conditional SyS mouse models that, after combination with some of the few other recurrent alterations, such as gains in BCL2, Wnt-β-catenin signaling, FGFR family, or loss of PTEN and SMARCB1, have provided additional insight into the mechanisms of synovial sarcomagenesis. The recent advancements in the understanding of SyS biology and improvements in preclinical modeling pave the way to the development of new epigenetic drugs and immunotherapeutic approaches conducive to new treatment options.

HER2-targeted therapies have revolutionized the treatment of HER2-positive breast cancer patients, leading to significant improvements in tumor response rates and survival. However, resistance and incomplete response remain considerable challenges. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a novel therapeutic strategy for the management of dyslipidemia by enhancing the clearance of low-density lipoprotein cholesterol receptors, however recent evidence also shows links between PCSK9 and cancer cells. We present an innovative immunization approach combining capsid virus-like particle (cVLP)-based vaccines against HER2 and PCSK9. The therapeutic activity of the combined vaccine was evaluated in female mice challenged with HER2-positive mammary carcinoma cells. Controls included untreated mice and mice treated with cVLP-PCSK9 and cVLP-HER2 as standalone therapies. Antibodies elicited by vaccinations were detected through ELISA immunoassay. The functional activity of the antibodies was tested in 3D-soft agar assay on human HER2 + + + trastuzumab sensitive and resistant cells. Mice vaccinated with cVLP-HER2 + cVLP-PCSK9 displayed tumor regression from the 40th day after cell challenge in 100% of mice remaining tumor-free even 4 months later. In contrast, 83% of mice treated with cVLP-HER2 vaccine alone experienced an initial tumor regression, followed by tumor relapse in 60% of subjects. Untreated mice and mice treated with the cVLP-PCSK9 vaccine alone developed progressive tumors within 1–2 months after cell injection. The combined vaccine approach elicited strong anti-human HER2 antibody responses (reaching 1–2 mg/ml range) comprising multiple immunoglobulins isotypes. cVLP-PCSK9 vaccine elicited anti-PCSK9 antibody responses, resulting in a marked reduction in PCSK9 serum levels. Although the anti-PCSK9 response was reduced when co-administered with cVLP-HER2, it remained significant. Moreover, both cVLP-HER2 + cVLP-PCSK9 and cVLP-HER2 alone induced anti-HER2 antibodies able to inhibit the 3D growth of human HER2 + + + BT-474 and trastuzumab-resistant BT-474 C5 cells. Strikingly, antibodies elicited by the combined vaccination were more effective than those elicited by the cVLP-HER2 vaccine alone in the inhibition of trastuzumab-resistant C5 cells. The results indicate that cVLP-PCSK9 vaccination shows adjuvant activity when combined with cVLP-HER2 vaccine, enhancing its therapeutic efficacy against HER2-positive breast cancer and holding promise in overcoming the challenges posed by resistance and incomplete responses to HER2-targeted therapy.

IL-1 family members have multiple pleiotropic functions affecting various tissues and cells, including the regulation of the immune response, hematopoietic homeostasis, bone remodeling, neuronal physiology, and synaptic plasticity. Many of these activities are involved in various pathological processes and immunological disorders, including tumor initiation and progression. Indeed, IL-1 family members have been described to contribute to shaping the tumor microenvironment (TME), determining immune evasion and drug resistance, and to sustain tumor aggressiveness and metastasis. This review addresses the role of IL-1 family members in bone sarcomas, particularly the highly metastatic osteosarcoma (OS) and Ewing sarcoma (EWS), and discusses the IL-1-family-related mechanisms that play a role in bone metastasis development. We also consider the therapeutic implications of targeting IL-1 family members, which have been proposed as (i) relevant targets for anti-tumor and anti-metastatic drugs; (ii) immune checkpoints for immune suppression; and (iii) potential antigens for immunotherapy.