Immunogenic cell death (ICD) elicited by cancer therapy reshapes the tumor immune microenvironment. A long-term adaptative immune response can be initiated by modulating cell death by therapeutic approaches. Here, the major hallmarks of ICD, endoplasmic reticulum (ER) stress, and damage-associated molecular patterns (DAMPs) are correlated with ICD inducers used in clinical practice to enhance antitumoral activity by suppressing tumor immune evasion. Approaches to monitoring the ICD triggered by antitumoral therapeutics in the tumor microenvironment (TME) and novel perspective in this immune system strategy are also reviewed to give an overview of the relevance of ICD in cancer treatment.

Specific anti-tumor immune responses have proven to be pivotal in shaping tumorigenesis and tumor progression in solid cancers. These responses can also be of an autoimmune nature, and autoantibodies can sometimes be present even before the onset of clinically overt disease. Autoantibodies can be generated due to mutated gene products, aberrant expression and post-transcriptional modification of proteins, a pro-immunogenic milieu, anti-cancer treatments, cross-reactivity of tumor-specific lymphocytes, epitope spreading, and microbiota-related and genetic factors. Understanding these responses has implications for both basic and clinical immunology. Autoantibodies in solid cancers can be used for early detection of cancer as well as for biomarkers of prognosis and treatment response. High-throughput techniques such as protein microarrays make parallel detection of multiple autoantibodies for increased specificity and sensitivity feasible, affordable, and quick. Cancer immunotherapy has revolutionized cancer treatments and has made a considerable impact on reducing cancer-associated morbidity and mortality. However, immunotherapeutic interventions such as immune checkpoint inhibition can induce immune-related toxicities, which can even be life-threatening. Uncovering the reasons for treatment-induced autoimmunity can lead to fine-tuning of cancer immunotherapy approaches to evade toxic events while inducing an effective anti-tumor immune response.

Chimeric antigen receptor (CAR) T-cells targeting CD19 have shown impressive outcomes in refractory/relapsed B-cell acute lymphoblastic leukaemia (r/r B-ALL); however, frequent relapse demands multi-targeted approaches. We report Spanish clinical data on the safety and efficacy of tandem anti-CD19/CD22 CAR T-cells administered on a compassionate use basis in a cohort of 10 heavily pretreated paediatric, adolescent, and young adult (AYA) patients with r/r B-ALL. Most (9/10) of the patients had relapsed B-ALL, 7 having received previous anti-CD19 CAR T-cell therapy and 6 haematopoietic stem cell transplantation (HSCT). Two patients had Down syndrome. Increased high-grade CRS/ICANS and proinflammatory markers (IL-6, LDH and ferritin) correlated with patients with a high tumour burden (TB) before lymphodepletion. Complete remission on day +28 post-infusion was achieved in 8/10 patients (7 with MRD-), and 5/7 patients received HSCT as consolidative therapy within three months post-infusion. Two patients with early relapse after tandem anti-CD19/CD22 CAR received rescue therapy and HSCT. At the 18-month follow up, overall survival (OS) was 70% (95% CI, 47%–100%). Tandem anti-CD19/CD22 CAR T-cell administration combined with consolidative HSCT is a promising therapeutic approach, though managing bridging therapy and reducing the TB prior to infusion remain key challenges (REALL_CART trial, NCT06709469, EudraCT 2023-509723-41-01). This work was supported by a grant from the 10.13039/501100004587 Instituto de Salud Carlos III to APM PI22/01226, two grants from CRIS Cancer Foundation to Beat Cancer as part of the projects “Advanced Cell Therapy Unit Hospital Universitario La Paz” and JM “Proyecto Mateo: CAR T-cell therapy for juvenile myelomonocytic leukaemia” and “Terapia avanzada CAR-T CD19/CD22”, Ayuda Nominativa de la Consejería de Investigación, 10.13039/100012818 Comunidad de Madrid , Spain. Work in MI lab was funded by a grant from the 10.13039/501100004837 Spanish Ministry of Science and Innovation (PID2020-114148RB-I00). VGG was granted with Río Hortega (AES 2022 exp. Nº. CM22/00078) and Juan Rodés (AES 2024 exp. Nº. JR24/00003) contracts from the 10.13039/501100004587 Carlos III Health Institute (ISCIII) through the European Funds of the Recovery, Transformation and Resilience Plan and financed by the European Union NextGenerationEU.

Malignant bone tumors are aggressive tumors, with a high tendency to metastasize, that are observed most frequently in adolescents during rapid growth spurts. Pediatric patients with malignant bone sarcomas, Ewing sarcoma and osteosarcoma, who present with progressive disease have dire survival rates despite aggressive therapy. These therapies can have long-term effects on bone growth, such as decreased bone mineral density and reduced longitudinal growth. New therapeutic approaches are therefore urgently needed for targeting pediatric malignant bone tumors. Harnessing the power of the immune system against cancer has improved the survival rates dramatically in certain cancer types. Natural killer (NK) cells are a heterogeneous group of innate effector cells that possess numerous antitumor effects, such as cytolysis and cytokine production. Pediatric sarcoma cells have been shown to be especially susceptible to NK-cell-mediated killing. NK-cell adoptive therapy confers numerous advantages over T-cell adoptive therapy, including a good safety profile and a lack of major histocompatibility complex restriction. NK-cell immunotherapy has the potential to be a new therapy for pediatric malignant bone tumors. In this manuscript, we review the general characteristics of osteosarcoma and Ewing sarcoma, discuss the long-term effects of sarcoma treatment on bones, and the barriers to effective immunotherapy in bone sarcomas. We then present the laboratory and clinical studies on NK-cell immunotherapy for pediatric malignant bone tumors. We discuss the various donor sources and NK-cell types, the engineering of NK cells and combinatorial treatment approaches that are being studied to overcome the current challenges in adoptive NK-cell therapy, while suggesting approaches for future studies on NK-cell immunotherapy in pediatric bone tumors.

In the present work, leptomeningeal disease, a very destructive form of systemic cancer, was characterized from several proteomics points of view. This pathology involves the invasion of the leptomeninges by malignant tumor cells. The tumor spreads to the central nervous system through the cerebrospinal fluid (CSF) and has a very grim prognosis; the average life expectancy of patients who suffer it does not exceed 3 months. The early diagnosis of leptomeningeal disease is a challenge because, in most of the cases, it is an asymptomatic pathology. When the symptoms are clear, the disease is already in the very advanced stages and life expectancy is low. Consequently, there is a pressing need to determine useful CSF proteins to help in the diagnosis and/or prognosis of this disease. For this purpose, a systematic and exhaustive proteomics characterization of CSF by multipronged proteomics approaches was performed to determine different protein profiles as potential biomarkers. Proteins such as PTPRC, SERPINC1, sCD44, sCD14, ANPEP, SPP1, FCGR1A, C9, sCD19, and sCD34, among others, and their functional analysis, reveals that most of them are linked to the pathology and are not detected on normal CSF. Finally, a panel of biomarkers was verified by a prediction model for leptomeningeal disease, showing new insights into the research for potential biomarkers that are easy to translate into the clinic for the diagnosis of this devastating disease.