AIM:This study aimed to investigate the role of the tumor microenvironment in two key aspects of cancer progression: regulation of tumor cell motility and development of resistance to targeted therapy. METHODS:In vitro lung adenocarcinoma cell lines were used to assess the effects of hypoxia on cell migration, proliferation, signaling pathway activity, and expression of epithelial- mesenchymal transition (EMT) markers. RESULTS:Hypoxia reduced single-cell motility and proliferation while promoting collective invasion and inducing cell line-specific EMT-related changes. Hypoxia-mimicking CoCl2 treatment failed to reproduce the effects of true hypoxic conditions. In the second part of the study, a patient- derived tumor xenograft (PDTX) model of BRAF V600E mutant melanoma was established to investigate acquired resistance to vemurafenib. Bulk RNA sequencing identified potential resistance-associated markers, however, protein- level validation was inconclusive. CONCLUSIONS:Our results highlight that both hypoxia and therapeutic pressure modulate tumor progression in a complex, context-dependent manner.
Cancer drug resistance remains one of the greatest barriers to durable therapeutic success. Here, we reframe resistance as a dynamic landscape shaped by transporter‑mediated efflux, reversible drug‑tolerant persister states, and therapy‑induced senescence. This review highlights areas where our group has made substantial contributions, with a particular focus on our own experimental and conceptual advances. We show how P‑glycoprotein (P-gp) overexpression, traditionally viewed as an obstacle sustaining cancer multidrug resistance (MDR), creates exploitable metabolic vulnerabilities, enabling the development of MDR‑selective compounds. We demonstrate that persister cells rely on transient P‑gp-mediated detoxification, revealing a therapeutic window during drug‑free intervals. We further show that senescence is not a terminal fate but a relapse‑initiating state requiring targeted intervention. Finally, we illustrate how pharmacokinetics and dosing schedules can be harnessed to reshape tumor evolution, culminating in LiPyDau, a next‑generation liposomal anthracycline with durable activity against resistant tumors. Together, these insights outline a unified strategy for anticipating, intercepting, and ultimately overcoming cancer drug resistance.
Targeting the cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, also named TXNRD1) has emerged as a promising strategy to exploit redox vulnerabilities in cancer. However, both preclinical observations and recent mechanistic studies indicate that TrxR1 inhibition can have context‑dependent outcomes. This article synthesizes a mechanistic framework linking cytosolic redox buffering, proteostasis, receptor tyrosine kinase (RTK) signaling, and immune surveillance with treatment responses. It highlights the dual functional roles of the TrxR1-substrate TXNL1 (also named TRP32), discusses intracellular transcriptional crosstalk shaping treatment sensitivity, and outlines potential combination strategies with RTK modulators.
AIM:Tumor hypoxia is a major driver of tumor progression and metastasis. Hypoxic adaptation is regulated by hypoxiainducible factor-1 (HIF-1), which controls the transcription of genes promoting malignant behavior. HIF-1 inhibitors have failed as monotherapies in clinical trials, highlighting the need for combination-based strategies. This study aimed to develop hypoxia-targeted combination therapies for breast and ovarian cancers. METHODS:Using established in vitro and in vivo hypoxia models, we evaluated acriflavine, a HIF-1 inhibitor, in combination with paclitaxel and an epithelial-mesenchymal transition targeting agent. RESULTS:Acriflavine exerted potent antiproliferative effects, particularly in triple-negative breast cancer cell lines, and proteomic profiling indicated modulation of migration, proliferation, and cellular metabolism. The acriflavine-paclitaxel combination showed synergistic antitumor and antimetastatic activity, which was further enhanced by rolipram. CONCLUSIONS:Overall, our findings support hypoxia-targeted combination approaches and provide a biological rationale for combining HIF-1 inhibition with immune checkpoint blockade in breast cancer.
Glucocorticoids, most commonly dexamethasone, are widely used alongside breast cancer therapy to alleviate adverse effects of chemotherapy, particularly allergic reactions and nausea. However, growing evidence shows that the activation of the glucocorticoid receptor (GR) has context-dependent effects on tumour biology, with both tumour-suppressive and tumour-promoting consequences. This review summarises the molecular basis of GR signalling in breast cancer and its prognostic relevance across molecular subtypes. Particular emphasis is placed on ligand-dependent and ligand-independent GR activation, crosstalk with the oestrogen receptor and GR-regulated transcriptional programmes associated with tumour cell migration and therapy resistance. Overall, the available evidence suggests that the use of glucocorticoids in triple-negative breast cancer is not biologically neutral. Assessment of GR using methods such as routine immunohistochemistry may add future value for patient's stratification for GR-targeted therapy and could inform more personalised supportive treatment and follow-up strategies; however, these approaches require prospective validation before clinical implementation.
AIM:Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy in which serum calcitonin plays a pivotal role in early diagnosis, surgical planning, guidance of systemic therapy, and monitoring of treatment response. This case highlights the importance of laboratory diagnostics during selpercatinib therapy in a patient with disseminated MTC harboring a rare RET pathogenic variant. METHODS:A cervical vertebral fracture in a young, asymptomatic male revealed MTC metastasis with distant dissemination and markedly elevated serum CEA and calcitonin levels. Tumor tissue and circulating DNA analysis identified the rare p.Glu632_Leu633del RET mutation. No germline alteration was detected. First-line systemic therapy comprised the selective RET tyrosine kinase inhibitor selpercatinib combined with denosumab. RESULTS:Rapid clinical improvement occurred without significant adverse effects. Serum calcitonin levels normalized within four weeks, and imaging revealed marked tumor regression. CONCLUSION:This case underscores the value of liquid biopsy detected mutations in guiding targeted therapy. Clinical, biochemical, and radiological findings support the potential use of selective RET tyrosine kinase inhibitors for this rare mutation. Serum calcitonin serves as a reliable quantitative biomarker of therapeutic efficacy.
Psychological stress and cancer are frequently framed in causal narratives in public discourse; however, current scientific evidence does not support such assumptions. Epidemiological and prospective cohort studies indicate that psychological stress cannot be established as an independent carcinogenic factor, and population-level associations between stress and cancer incidence are consistently absent. Certain psychosocial variables, including maladaptive coping strategies or persistent high-level distress, show moderate and inconsistent associations with clinical outcomes (e.g., survival, recurrence), but these findings are heterogeneous and subject to methodological limitations. Psycho-oncological interventions effectively reduce psychological distress and improve quality of life, while direct causal effects on tumor progression remain unproven. Accordingly, psychosocial care is clinically warranted, contributing to patient well-being and adaptive coping, while clearly distinguishing these effects from biological causal pathways.
Cancer metabolism is a central field in oncology, strongly serving as critical adaptation mechanism driving tumour progression, therapeutic response, and patient prognosis. The complexity of tumour metabolism remains difficult to mimic using conventional experimental conditions. Preclinical models, including in vitro 2D cultures and in vivo animal models, often fail to accurately reproduce the dynamic tissue alterations. Increasing evidence highlights the crucial role of the tumour microenvironment, nutrient availability, hypoxia, extracellular matrix components, and metabolic crosstalk between cancer, stromal, and immune cells in shaping tumour metabolic rewiring. Consequently, advanced 3D culture systems have gained significant attention, offering new perspectives for modelling cellular complexity and metabolic heterogeneity. This review summarises metabolic adaptation mechanisms influenced by microenvironment, and discusses the evolution of current modelling. Furthermore, through our own research in 3D bioprinting, we highlight the emerging role of 3D bioprinted models in tumour biology, cancer metabolism research and drug sensitivity studies.
HER2-targeted therapies have improved outcomes in solid tumors, but their efficacy is often limited by resistance and tumor microenvironmental barriers. Over the past decade, the University of Debrecen Cell and Molecular Therapy Research Group has focused on developing CAR-engineered immune cell strategies to address these challenges. Our work spans advances in CAR-T cell design, including optimization of costimulatory signaling, development of modular targeting systems, and expansion toward off-the-shelf platforms such as CAR-NK cells. Collectively, these efforts highlight the potential of engineered immune cells to overcome key limitations of conventional therapies and support the continued evolution of CAR-based approaches for solid tumors.
Immune-related dermatologic side effects are among the most common and often the earliest toxicities of immunotherapies. Clinically, they cover a wide spectrum, ranging from mild skin symptoms to severe, life-threatening conditions. Most cases can be well managed with early recognition and personalized treatment. The dermatologist plays a key role in rapid diagnosis, therapeutic decision-making, and multidisciplinary oncological collaboration. The goal of supportive oncodermatology is, in addition to controlling side effects, to ensure the continuation of immunotherapy and to preserve the patient's quality of life.
Breast cancer is the most common malignancy in women worldwide, with triple-negative breast cancer (TNBC) posing the greatest therapeutic challenge due to limited treatment options and high recurrence rates. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has redefined management in TNBC, with pembrolizumab now a standard of care in both early-stage and metastatic settings. Emerging strategies, including cancer vaccines, adoptive cellular therapies, and combination immunotherapies are under investigation, and yet to demonstrate clinical benefit. Key unmet needs include biomarker development for better patient selection and prediction of risk for immune related adverse events, as well as rapid diagnosis, and management of immune-related toxicities. Despite these challenges, immunotherapy offers transformative potential to improve outcomes in breast cancer.
Skin cancers are the most commonly diagnosed malignancies worldwide; however, effective treatment of advanced tumors was unavailable until recent years. In the past decade, the introduction of immune checkpoint inhibitors (ICIs), targeting CTLA-4, PD-1, PD-L1 and recently LAG-3, has revolutionized therapeutic strategies for advanced skin cancers and improved survival outcomes. In this review, we present the current therapeutic opportunities and future directions of immunotherapy in the management of malignant melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma, and Merkel cell carcinoma, accompanied by a brief overview of their mechanisms of action. Ambrus L, Balatoni T. Immunotherapy of cutaneous neoplasms.
Gastroesophageal cancers still rank among the leading causes of cancer-related death. With the introduction of immunotherapy, the treatment strategy has evolved. In the neoadjuvant setting for gastroesophageal junction (GEJ) and gastric adenocarcinoma, the results of the MATTERHORN clinical trial, presented at this year's ASCO meeting, are expected to shift future treatment strategies. In esophageal tumors, adjuvant nivolumab is used. In metastatic disease, depending on the histological subtype, molecular testing such as PD-L1 CPS and TPS, HER2, and MSI-H is required to determine the treatment decision. In the metastatic setting, combinations of nivolumab or pembrolizumab with fluoropyrimidine- and platinum-based chemotherapy have improved survival. Among HER2-positive patients, adding pembrolizumab to trastuzumab and chemotherapy - in PDL1 CPS ≥1 cases - has become a new standard. A special mention must be made of MSI-H tumors, in which immunotherapy is highly effective, and adjuvant chemotherapy is not recommended according to current guidelines.
AIM:To review the development of immunotherapy (IO) for urological cancers (urothelial carcinoma - UC, renal cell carcinoma - RCC, prostate cancer - PCa , testicular germ cell tumors - TGCT) with a focus on the latest studies, combination strategies, and the messages of the 2025 guidelines. METHODS:Review of randomized phase II-III studies published in 2024-2025, international guidelines, and biomarker- guided approaches. RESULTS:In UC, the combination of enfortumab vedotin and pembrolizumab has been a breakthrough and has become the new first-line standard, while maintenance and adjuvant immunotherapies have also been strengthened. In RCC, IO- TKI and IO-IO combinations show long-term survival benefits, but the IO-after-IO strategy has proven questionable. In PCa, the efficacy of immunotherapy is mainly limited to biomarker-driven subgroups (MSI-H/dMMR), while in TGCT, cisplatin-based treatment remains the standard, and the role of IOs is being evaluated in further studies. CONCLUSIONS:By 2025, immunotherapy has become the therapeutic basis for UC and RCC, both in metastatic and curative treatments. In PCa and TGCT, immunotherapy options remain in the experimental phase, but research is ongoing with new combinations and biomarker-driven strategies.
Immune checkpoint inhibitors (ICIs) have brought a major breakthrough in the treatment of malignant tumors. However, the use of ICIs has led to the emergence of new, previously unknown side effects in oncology. These agents disrupt immunological homeostasis and reduce T-cell tolerance, which can lead to the activation of autoreactive T-cells, causing various immune-related adverse events (irAEs). Side effects affecting endocrine organs develop relatively frequently with immunotherapy, affecting approximately 10% of patients. Any endocrine organ, or even several at the same time, can be damaged (autoimmune polyendocrine syndrome, APS). The most commonly affected organs are the thyroid and pituitary glands, but the adrenal glands, pancreas, and parathyroid glands can also be affected. The treatment of endocrine side effects differs fundamentally from that of other irAEs in three ways: highdose corticosteroid treatment is not required (except for hypophysitis causing visual complaints and thyrotoxic crisis); damage to endocrine organs is usually permanent, requiring lifelong hormone replacement; permanent discontinuation of ICI therapy is usually not necessary even in severe cases, as it is of no benefit due to the already established irreversible damage. Our aim is to review endocrine adverse events caused by ICIs, their symptoms, diagnosis, and provide guidance on the management of these adverse events.
The advent of immune checkpoint inhibitors has brought a major breakthrough in the treatment of solid tumors, particularly in non-small cell lung cancer, melanoma, renal cell carcinoma, and bladder cancer. However, the use of these agents has also been associated with the emergence of a new type of side effect profile, among which pulmonary complications are of outstanding importance. The most frequent and severe of these is immune-related pneumonitis, a potentially life-threatening condition. Clinical symptoms are often nonspecific and may mimic other respiratory or infectious diseases, posing a diagnostic challenge in daily practice. Rapid recognition, careful differential diagnosis, and appropriate management are crucial for treatment continuity and patient safety. The aim of this article is to provide a comprehensive overview of pulmonary immune-related adverse events, to present their clinical and radiological characteristics, and to review current treatment recommendations.
The spectacular development of radiotherapy technology in the twenty-first century and the everyday availability of this modern technique have founded the possibility of combining radiotherapy with various systemic oncological treatments with increasing safety and effectiveness. The most novel systemic treatment modality, the modern immunotherapy, which is also the achievement of the present century, and the latest milestone in its rapid spread across the therapeutic spectrum in cancer care is the step forward to the treatment of earlier tumor stages with curative intent. The inevitable meeting point of these rapidly developing treatment modalities is the care of locally advanced tumors, achieving the theory and practice of the combination of immunotherapy with definitive radiotherapy. The success of the PACIFIC, ADRIATIC or KEYNOTE-A18 studies proves that further progress is possible in the definitive, curative treatment of locally advanced cancer diseases. In this paper, we describe this combination therapy algorithm, the biological background and the successful or less successful clinical trial results in the most relevant and important tumor types and indications.
In the case of non-small cell lung cancer, systemic treatment plays a key role in early, locally advanced as well as metastatic stages. The neoadjuvant approach is represented by the combination of immunotherapy+chemotherapy, while targeted therapy does not yet have an evidence-based place in this indication. Immune checkpoint inhibitor treatment has an important role in clinical practice in adjuvant setting as well. Several trials have also concluded with positive results regarding perioperative immunotherapy. Currently, the role of the multidisciplinary tumor board in the personalized decision-making process is essential. In locally advanced cases, immunotherapy after radiochemotherapy is also evidence-based. In advanced, non oncogene-addicted non-small cell lung cancer, the place of immunotherapy is well defined, both as monotherapy and in combination with chemotherapy. Progress has also been made in small cell lung cancer, both in extensive and limited stages, with immune checkpoint inhibitor treatment.
AIM:To summarize the clinical presentation, diagnosis, and therapy of immune checkpoint inhibitor (ICI) induced rare but severe cardiac adverse events, focusing primarily on immune- mediated myocarditis, and also a case presentation of one of our patients. METHODS:Based on a review of the literature and clinical experience, we present the pathophysiology, diagnostic steps, and treatment options for ICI-induced myocarditis. RESULTS:Myocarditis is associated with high mortality and is difficult to diagnose, as symptoms are nonspecific and the sensitivity of laboratory, imaging, and invasive tests varies. Following early diagnosis, high-dose steroid therapy can significantly improve survival. CONCLUSIONS:With the increasing use of ICI therapies, the recognition and management of severe cardiotoxic adverse events require a multidisciplinary approach and prompt intervention. Further prospective studies are needed to establish standardized therapeutic guidelines.
With the increasing use of immunotherapy, numerous gastroenterological side effects may occur, significantly impacting patients' quality of life and potentially leading to life-threatening complications. The most common adverse effects include diarrhea, colitis, hepatitis, pancreatitis, but other gastrointestinal manifestations such as those affecting the upper digestive tract and celiac disease have also been reported. Rapid recognition and intervention are crucial for improving patient outcomes, with corticosteroids being the primary treatment option, and various biological therapies are available depending on the specific side effect. This article provides a detailed analysis of the diagnostic and therapeutic approaches for common side effects, facilitating the exclusion of other etiologies and enabling effective treatment planning.
