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The “Tumor Immunology Meets Oncology” (TIMO XIX) meeting 2025 reports on the rapidly growing field of basic, but in particular translational tumor immunology thereby providing deeper insights into the heterogeneity of tumors, their microenvironment and clinical relevance. This represents the basis for the development of novel immunotherapeutic strategies and combinatorial therapies.

Treatment of cancer patients has been recently revolutionized by the application of various immunotherapeutics. However, the response rates are still limited ranging between approximately 20 and 40% suggesting that combinations of immunotherapy with conventional treatment, like chemotherapy, radiation, epigenetic modulators, targeted therapies using small molecules as well as other (immuno) therapeutics, might be an option to increase systemic anti-tumor immunity. It is postulated that different non-immune based therapies in combination with immunotherapies could reprogram the immune suppressive tumor microenvironment and enhance the immunogenicity of tumor cells leading to an improved therapeutic efficacy and a better patients' outcome. Despite there exist various examples of increased objective responses achieved by adding these different therapies to immunotherapies, strategies for rational and evidence-based design of checkpoint inhibitor combinations to maximize the clinical benefit for patients are urgently required. Therefore, the main purpose of this review is to summarize recent results obtained from experimental models and clinical trials to enhance tumor immunogenicity by combining immunotherapy with other therapeutic options to maximize patients' outcome and minimize adverse events.

It is obvious that tumor cells have developed a number of strategies to escape immune surveillance including an altered expression of various immune checkpoints, such as the programmed death-1 receptor (PD-1) and its ligands PD-L1 and PD-L2. The interaction between PD-1 and PD-L1 results in an activation of self-tolerance pathways in both immune cells as well as tumor cells. Thus, these molecules represent excellent targets for T cell-based immunotherapies. However, the efficacy of therapies using checkpoint inhibitors is variable and only a limited number of patients receive a long-term response, while others develop resistances. Therefore, a better insight into the constitutive expression levels and their control as well as the predictive and prognostic value of PD-1/PD-L1, which are controversially discussed due to the methodological assessment, the dynamic and time-related variable expression of these molecules, is urgently required. In this review, the current knowledge of the PD-L1 and PD-1 genes, their expression in immune and tumor cells, the underlying molecular mechanisms of their regulation and their association with clinical parameters and therapy responses are summarized.

The TIMO meeting XVIII 2024 covered both basic and translational tumor immunological topics, which were presented by national and international scientists and clinicians.

During the last decade, the dynamics of the cellular crosstalk have highlighted the significance of the host vs. tumor interaction. This resulted in the development of novel immunotherapeutic strategies in order to modulate/inhibit the mechanisms leading to escape of tumor cells from immune surveillance. Different monoclonal antibodies directed against immune checkpoints, e.g., the T lymphocyte antigen 4 and the programmed cell death protein 1/ programmed cell death ligand 1 have been successfully implemented for the treatment of cancer. Despite their broad activity in many solid and hematologic tumor types, only 20-40% of patients demonstrated a durable treatment response. This might be due to an impaired T cell tumor interaction mediated by immune escape mechanisms of tumor and immune cells as well as alterations in the composition of the tumor microenvironment, peripheral blood, and microbiome. These different factors dynamically regulate different steps of the cancer immune process thereby negatively interfering with the T cell -mediated anti-tumoral immune responses. Therefore, this review will summarize the current knowledge of the different players involved in inhibiting tumor immunogenicity and mounting resistance to checkpoint inhibitors with focus on the role of tumor T cell interaction. A better insight of this process might lead to the development of strategies to revert these inhibitory processes and represent the rational for the design of novel immunotherapies and combinations in order to improve their efficacy.

Natural killer (NK) cells belong to the family of innate immune cells with the capacity to recognize and kill tumor cells. Different phenotypes and functional properties of NK cells have been described in tumor patients, which could be shaped by the tumor microenvironment. The discovery of HLA class I-specific inhibitory receptors controlling NK cell activity paved the way to the fundamental concept of modulating immune responses that are regulated by an array of inhibitory receptors, and emphasized the importance to explore the potential of NK cells in cancer therapy. Although a whole range of NK cell-based approaches are currently being developed, there are still major challenges that need to be overcome for improved efficacy of these therapies. These include escape of tumor cells from NK cell recognition due to their expression of inhibitory molecules, immune suppressive signals of NK cells, reduced NK cell infiltration of tumors, an immune suppressive micromilieu and limited in vivo persistence of NK cells. Therefore, this review provides an overview about the NK cell biology, alterations of NK cell activities, changes in tumor cells and the tumor microenvironment contributing to immune escape or immune surveillance by NK cells and their underlying molecular mechanisms as well as the current status and novel aspects of NK cell-based therapeutic strategies including their genetic engineering and their combination with conventional treatment options to overcome tumor-mediated evasion strategies and improve therapy efficacy.

Despite the recent implementation of immunotherapies into clinical practice of various tumor types, the immunobiology of tumors and in particular the role and clinical relevance of the different immune cell populations and their function still remained unclear. Therefore, an in depth analysis of the complex landscape of immune cell populations and their soluble mediators in the peripheral blood and tumor microenvironment of cancer patients is urgently needed. Mass cytometry has revolutionized the immune phenotyping in particular in settings where simultaneous breadth and detailed characterization of the phenotype and function of immune cell (sub)populations with limited sample size is required, such as monitoring of patients’ response to immunotherapies. Since mass cytometry is a powerful multiplex approach to decipher tumor intrinsic and tumor extrinsic effects of tumor immunotherapies, this review summarizes the use of this technology for determination of the frequency and functional status of immune cell populations within the tumor and in the blood leading to the identification of intratumoral/peripheral immune signatures that might serve as biomarkers (i) for treatment response and/or failure, (ii) for the stratification of tumor patients or (iii) for the identification of novel therapeutic targets.

Background The type III interferon family, known as interferon lambda (IFN-λ), consists of four isoforms (IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4) and plays essential roles in immune responses. It mediates anti-viral and anti-tumoral activities and is distinguished from type I and type II interferons (IFNs) by its interaction with a unique receptor complex involving IFN-λR1 and IL-10 Rβ predominantly expressed on epithelial cells and selected immune cell populations. This interaction results in activation of the JAK-STAT signaling pathway and transcription of interferon-stimulated genes (ISGs). Main body IFN-λs exert anti-viral activities, particularly at epithelial and barrier surfaces, and have emerged as therapeutic agents for chronic viral infections like hepatitis C virus and influenza, providing an alternative to traditional IFN therapies with a more favorable safety profile. Beyond these anti-viral properties, IFN-λs contribute to tumor control by enhancing immune surveillance and modulating the composition of the tumor microenvironment. However, accumulating evidence indicates that IFN-λ cells may also exhibit pro-tumorigenic potential by promoting immune evasion and tumor progression in certain contexts. These opposing functions underscore the complexity of IFN-λ biology and the need for further research to elucidate the mechanisms governing its actions, identify biomarkers that predict IFN response and to develop targeted strategies that maximize its therapeutic benefits, while minimizing adverse effects. Conclusion By elucidating the complex interplay between IFN-λ and the immune system, this review provides insights into its dual functions in immune-related diseases, its potential as a biomarker for disease monitoring and prediction of therapy response, and its potential for the development of targeted therapies in cancer treatment and viral infections. However, to improve the patients’ outcomes in infectious diseases and cancer management, a comprehensive understanding of its context-specific effects is required to optimize its clinical application.

Despite targeted therapies and immunotherapies have revolutionized the treatment of cancer patients, only a limited number of patients have long-term responses. Moreover, due to differences within cancer patients in the tumor mutational burden, composition of the tumor microenvironment as well as of the peripheral immune system and microbiome, and in the development of immune escape mechanisms, there is no “one fit all” therapy. Thus, the treatment of patients must be personalized based on the specific molecular, immunologic and/or metabolic landscape of their tumor. In order to identify for each patient the best possible therapy, different approaches should be employed and combined. These include (i) the use of predictive biomarkers identified on large cohorts of patients with the same tumor type and (ii) the evaluation of the individual tumor with “omics”-based analyses as well as its ex vivo characterization for susceptibility to different therapies.

Tumor immune escape plays a critical role in cancer, but the mechanisms involved in this process have still to be defined. In the recent years, progress has been made in understanding how peptides presented by MHC class I molecules were generated, in particular which proteases are involved in this process and how intracellular pathways influence antigen presentation in professional antigen-presenting cells and in various types of malignancies. Different MHC class I abnormalities have been found in solid tumors of distinct origin, but also in hematopoietic diseases. These include structural alterations such as total, haplotype and allelic loss of the MHC class I heavy chain, deletions and point mutations, in particular in β 2 -microglobulin and TAP1 as well as dysregulation of various components of the MHC class I antigen processing machinery (APM), which could occur at the epigenetic, transcriptional and posttranscriptional level. The lack or downmodulation of the expression of single or multiple components of the MHC class I antigen processing pathway may avoid the recognition of tumor cells by tumor-specific CD8 + cytotoxic T lymphocytes. This review will give an overview of the underlying molecular mechanisms of MHC class I abnormalities in human tumors of distinct histology, which also might have an impact on the design of T cell-based immunotherapies.