The utilization of immune checkpoint inhibitors has fundamentally changed both the treatment landscape for a multitude of malignancies as well as our understanding of cancer biology. Despite profound advancements, the utilization of these drugs is often limited by the development of immune-related adverse events (irAEs), characterized by off-target toxicity to healthy tissue secondary to treatment. Currently, irAEs are often treated with high-dose corticosteroids, with additional immunosuppressive agents added for severe or refractory irAEs. Cytokine pathway inhibitors, particularly anti-TNFa and anti-IL-6R antibodies, are commonly used as second-line immunosuppression. The efficacy of blocking these pathways in treating irAEs, as well as their potential impact on anti-tumor response, will be discussed. Additionally, this review will also explore other cytokines implicated in irAE pathophysiology, including interleukin-17 (IL-17), interleukin-23 (IL-23), interleukin-4/13 (IL-4/IL-13) and interleukin-5 (IL-5) which play important roles in the inflammatory cascades underlying specific irAEs such as colitis, dermatitis, and eosinophilia-related toxicities.

Cytokines are crucial modulators of immune responses and have emerged as key components in cancer immunotherapy, particularly concerning Natural Killer (NK) cells. Indeed, the administration of these cytokines have demonstrated significant therapeutic potential in clinical settings. For instance, interleukin-2 (IL-2) has shown efficacy in melanoma and renal cell carcinoma, enhancing anti-tumor immunity but often associated with dose-limiting toxicities. IL-12 has been linked to improved survival rates in various solid tumors by stimulating Th1 responses and activating NK cells. Additionally, IL-15 has gained recognition for its ability to enhance NK cell proliferation and persistence, translating into favorable clinical outcomes in hematological malignancies such as acute myeloid leukemia (AML). Remarkably, cytokines can act synergistically providing stronger effects, and recent advancements have led to the identification of cytokine-induced memory-like NK (CIML-NK) cells. Despite these advancements, significant challenges persist in the translation of cytokine and NK cell therapies into routine clinical practice. The short half-life of recombinant cytokines poses limitations on their effectiveness, requiring high doses that can lead to severe side effects. Additionally, the complexities involved in the large-scale production of cytokines and the development of GMP-grade NK cell-therapies must be overcome. Innovative delivery systems, such as heterodimeric fusion proteins, oncolytic viruses and cytokine gene therapy, have emerged to address these issues, yet further research is needed to optimize these approaches. Collectively, this review underscores the importance of cytokines in harnessing the full potential of NK cells for cancer immunotherapy, and ongoing efforts that aim to optimize cytokine delivery strategies and enhance NK cell manufacturing processes.

Cytokines regulate both innate and adaptive immunity, thus bridging these two types of immune response. Initially explored as standalone cancer therapies, their use was hindered by the unfavorable pharmacokinetic profiles of recombinant molecules and the competition from newer, more promising immunotherapies. However, with the advent of bioengineered cytokines featuring extended half-lives and reduced off-target effects, their therapeutic potential is being re-evaluated, especially in combination with monoclonal antibodies, immune checkpoint inhibitors, cancer vaccines, and advanced cellular therapies. Regarding cellular therapies, cytokines can be used to enhance the ex vivo expansion of therapeutic bioproducts or improve their in vivo persistence and function. In the context of allogeneic hematopoietic stem cell transplantation, cytokines may support immune reconstitution, thereby reducing the risk of serious infections and disease recurrence. The immunomodulatory role of cytokines is particularly relevant in hematolymphoid malignancies, given the rising incidence of these conditions and the increasing cumulative exposure to various classes of chemotherapeutic agents. Also, this happens in a context where there is a decline in immune function, particularly relevant in older adults and in those with other chronic illnesses. In this review, we examine recent advances in cytokine-based therapies for hematological malignancies, both as monotherapy and in combination with chemotherapeutic agents, immunomodulatory drugs, or advanced cellular therapies.

More than four decades have passed since the discovery of Transforming Growth Factor beta (TGF-β) in 1981, a pivotal cytokine with profound implications in cell biology and potential clinical interventions for physio-pathological processes including fibrosis, immune-related disorders, chronic infections, vascular alterations, and the progression of tumour growth through invasiveness and metastasis. However, the introduction of a specific inhibitor targeting this cytokine into the pharmaceutical market remains elusive. Various molecular entities and therapeutic strategies, including small molecules, peptides, recombinant proteins (such as specific antibodies), oligonucleotides, and cellular-based therapies have been devised and subjected to clinical trials. These target the specific TGF-β molecular pathway, either directly or indirectly. The combination of different drug types, routes of administration, and clinical indications has generated substantial data, emphasizing significant variability in patient outcomes. Efforts to enhance the effectiveness of cancer immunotherapy by combining TGF-β inhibitors with other drugs and modulating complementary molecular targets have been explored over the past few decades. This approach aims to translate the promising preclinical efficacy of TGF-β blockade into commercially available drugs that are suitable for a broad spectrum of clinical indications. However, a clear path to address the lack of discernible efficacy and overcome the associated marketing challenges has not yet emerged. This review provides a comprehensive overview of the clinical development and emerging trends in TGF-β inhibitors and modulatory strategies, offering novel perspectives for addressing this persistent challenge.

Cancer immunotherapy includes vaccines generated through distinct approaches, each with advantages and limitations. Those made of autologous or allogeneic whole cells do not require prior identification of antigens, that is, immunize against undetermined (agnostic) tumor antigens. However, they often exhibit low adjuvanticity and modest antigenicity. Viruses have emerged as elicitors and enhancers of immune responses. Oncolytic viruses are replicating anticancer agents, most often administered intratumorally. They derepress the immunosuppressive tumor microenvironment through different mechanisms, and some promote antitumor immunity-a strategy termed oncolytic immunotherapy. Tropism-retargeted oncolytic herpes simplex viruses (here ReHVs), generated in our laboratory, specifically target a tumor-associated antigen (TAA) of choice that serves as receptor for ReHV entry into the cancer cell. ReHVs do not cause off-target infections in preclinical models, are fully replication-competent and able to contrast the antiviral innate responses they elicit, and prime T cells against tumors.

We developed an ReHV-mediated immunotherapeutic platform (Re-IP) that consists of thymidine kinase-positive cancer cells ex vivo infected with ad hoc designed HER2-tropic ReHV implanted ectopically to immunize mice against cancer without direct tumor treatment.

In a therapeutic-like setting, Re-IP robustly primed anticancer T cells that infiltrated distant untreated tumors and inhibited their growth. Tumor growth inhibition required CD8+ cells. Re-IP vaccinated against both the gnostic TAA (here HER2) employed for ReHV retargeting and a broader repertoire of agnostic tumor antigens, also sensitizing tumors to checkpoint blockade. Ectopically implanted uninfected cancer cells failed to elicit an immune response, highlighting the adjuvant effect of ReHV infection. Re-IP was effective in herpes simplex virus (HSV)-preimmune mice, unlike systemic treatments with oncolytic HSVs, which are blunted by prior antiviral immunity. Re-IP safety rested in the absence of replicating virus in off-target tissues and in tumors whose growth was inhibited.

Ectopically administered Re-IP adjuvants cancer cells' immunogenicity without the need for direct tumor treatment. The induced T-cell immunity inhibits the growth of distant untreated tumors and remains effective in HSV-preimmune mice. In humans, this approach might be applied to elicit anticancer T-cell responses against hard-to-reach, unresectable, or metastatic lesions and to enhance immune cell activation and expansion in adoptive therapies.

Spontaneous canine prostate cancer (PC) is widely considered a pertinent clinical model for the human disease. While over 95% of PC in men are adenocarcinomas, arising from prostatic glandular epithelium, it is increasingly recognised that many canine PC are of urothelial origin, arising within the prostatic urethra or ducts, or through invasion from a primary urinary bladder tumour. At diagnosis, canine prostatic tumours are often poorly differentiated and widely disseminated, masking the primary site and limiting the sensitivity of cellular biomarkers. Consequently, published studies of canine PC show varying representation of glandular versus urothelial tumours, yielding conflicting observations regarding their molecular pathogenesis and clinical behaviour. We characterised DNA sequence mutations and copy number aberrations in 31 canine PC, seeking evidence supporting relevance as a disease model. Only three tumours resembled adenocarcinomas. The remainder were either histologically consistent with urothelial carcinoma (n = 15), showed mixed glandular and urothelial morphology (n = 4), or were carcinomas of undetermined cell type (n = 9). BRAF V588E mutation was detected in 87% of tumours, including all three adenocarcinomas. Urinary bladder involvement was evident in 46% of cases, but none of the adenocarcinomas. Genome-wide DNA copy number instability was apparent throughout the cohort, with chromosome 36 gain significantly associated with urothelial tumours. Hallmark alterations of human PC, such as defects within PI3K and androgen receptor signalling pathways, were not detected. Improved molecular subclassification of canine PC is needed to direct selection of relevant cases for modelling the human disease and to ensure appropriate extrapolation between canine and human studies.

PCOS is one of the most common endocrine disorders in reproductive-aged women, causing diverse clinical manifestations with significant long-term health impacts. This review provides contemporary epidemiological evidence on PCOS outcomes while highlighting methodological limitations and research priorities.

Polycystic ovary syndrome (PCOS) affects 10-13% of women worldwide and is characterized by metabolic, reproductive, dermatological and psychological manifestations with long-term health implications. The aetiology of PCOS is complex and multifactorial, involving genetic predisposition and environmentally driven increases in obesity, manifesting as hyperandrogenism and insulin resistance. Research has been underfunded in this condition with significant remaining knowledge gaps, particularly in its pathophysiology, heterogeneity, and long-term natural history. Epidemiological research is essential for understanding the natural history of this chronic and complex condition with current insight gaps and future directions outlined herein.

The surveillance protocol for early-stage non-small cell lung cancer (NSCLC) is not contingent upon individualized risk factors for recurrence. This study aimed to use comprehensive data from clinical practice to develop a deep-learning model for practical longitudinal monitoring.

A multimodal deep-learning model with transformers was developed for real-time recurrence prediction using baseline clinical, pathological, and molecular data with longitudinal laboratory and radiologic data collected during surveillance. Patients with NSCLC (stage I to III) who underwent surgery with curative intent between January 2008 and September 2022 were included. The primary outcome was predicting recurrence within 1 year after the monitoring point. This study demonstrates the timely provision of risk scores (RADAR score) and determined thresholds and the corresponding AUC.

A total of 14,177 patients were enrolled (10,262 with stage I, 2,380 with stage II, and 1,703 with stage III). The model incorporated 64 clinical-pathological-molecular factors at baseline, along with longitudinal laboratory and computed tomography imaging interpretation data. The mean baseline RADAR score was 0.324 (standard deviation [SD], 0.256) in stage I, 0.660 (SD, 0.210) in stage II, and 0.824 (SD, 0.140) in stage III. The AUC for predicting relapse within 1 year of the monitoring point was 0.854 across all stages, with a sensitivity of 86.0% and a specificity of 71.3% (AUC = 0.872 in stage I, AUC = 0.737 in stage II, and AUC = 0.724 in stage III).

This pilot study introduces a deep-learning model that uses multimodal data from routine clinical practice to predict relapses in early-stage NSCLC. It demonstrates the timely provision of RADAR risk scores to clinicians for recurrence prediction, potentially guiding risk-adapted surveillance strategies and aggressive adjuvant systemic treatment.

Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate comprised of a topoisomerase I inhibitor payload and a monoclonal antibody directed to trophoblast cell-surface antigen 2, a protein that is broadly expressed in several types of solid tumors. In the TROPION-Lung01 phase III trial (NCT04656652), Dato-DXd demonstrated statistically significant improvement in median progression-free survival (mPFS) over docetaxel (4.4 vs. 3.7 months, hazard ratio [HR]=0.75, 95% confidence interval [CI], 0.62-0.91, P=.004]) in patients with previously treated metastatic non-small cell lung cancer (mNSCLC). Improvement in PFS was demonstrated in patients with nonsquamous mNSCLC (mPFS: 5.5 vs. 3.6 months, HR = 0.63, 95% CI, 0.51-0.79) and those with NSQ mNSCLC and actionable genomic alterations (mPFS: 5.7 vs 2.6 months, HR = 0.35, 95% CI, 0.21-0.60). A pooled analysis of previously treated patients with epidermal growth factor receptor mutation-positive NSCLC from TROPION-Lung01 and TROPION-Lung05 (NCT04484142) treated with Dato-DXd supported clinical activity (mPFS: 5.8 months, 95% CI, 5.4-8.2). In the TROPION-Breast01 phase III trial (NCT05104866), Dato-DXd demonstrated statistically significant improvement in mPFS over the investigator's choice of chemotherapy (6.9 vs. 4.9 months, HR = 0.63, 95% CI, 0.52-0.76, P<.0001) in patients with previously treated post-endocrine therapy hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Dato-DXd also demonstrated a distinct safety profile in both trials. The successful implementation of any new anticancer therapy requires learning how to prevent, monitor, and manage treatment-related adverse events (AE). Information can be gained from real-world clinical practices, institutional approaches, and multidisciplinary teams who treat patients with Dato-DXd to provide a better patient experience and improved outcomes. Here, we discuss practical insights and management and treatment of key AEs from Dato-DXd, including oral mucositis/stomatitis, nausea and vomiting, ocular surface events, and interstitial lung disease garnered from a multidisciplinary team of health care professionals experienced in treating patients with Dato-DXd.

Pulmonary metastatic melanoma (PMM) is an aggressive malignancy with limited response and rapid resistance to clinical chemotherapy, radiotherapy, immunotherapy, and biological therapies. Here, we developed a targeted biomimetic drug delivery system, TP-siRC@tHyNPs, by fusing exosomes derived from engineered cells overexpressing DR5 single-chain variable fragments (DR5-Exo) with liposomes coencapsulating triptolide (TP) and CYP3A4-siRNA (TP-siRC@Lip). DR5-Exo facilitated the targeted delivery of drug to tumor cells through DR5 receptor recognition and simultaneously activated apoptotic pathways. Moreover, CYP3A4-siRNA effectively prolonged the half-life of TP, thereby enhancing its antiproliferative and pro-apoptotic effects. Mechanistic studies revealed that TP-siRC@tHyNPs induced immunogenic cell death, reprogrammed macrophage polarization, arrested cell cycle progression, and triggered apoptotic pathways. In vivo experiments demonstrated that TP-siRC@tHyNPs specifically accumulated in lung tissue, notably inhibiting the growth of PMM while exhibiting negligible toxicity in tumor-bearing mice. Overall, this study provides a promising strategy for targeting PMM treatment, improving therapeutic efficacy while reducing off-target toxicity.