Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Therefore, the need for new therapeutic strategies is still a challenge. Surgery and chemotherapy represent the first-line interventions; nevertheless, the prognosis for metastatic CRC (mCRC) patients remains unacceptable. An important step towards targeted therapy came from the inhibition of the epidermal growth factor receptor (EGFR) pathway, by the anti-EGFR antibody, Cetuximab, or by specific tyrosine kinase inhibitors (TKI). Cetuximab, a mouse–human chimeric monoclonal antibody (mAb), binds to the extracellular domain of EGFR thus impairing EGFR-mediated signaling and reducing cell proliferation. TKI can affect the EGFR biochemical pathway at different steps along the signaling cascade. Apart from Cetuximab, other anti-EGFR mAbs have been developed, such as Panitumumab. Both antibodies have been approved for the treatment of KRAS-NRAS wild type mCRC, alone or in combination with chemotherapy. These antibodies display strong differences in activating the host immune system against CRC, due to their different immunoglobulin isotypes. Although anti-EGFR antibodies are efficient, drug resistance occurs with high frequency. Resistant tumor cell populations can either already be present before therapy or develop later by biochemical adaptations or new genomic mutations in the EGFR pathway. Numerous efforts have been made to improve the efficacy of the anti-EGFR mAbs or to find new agents that are able to block downstream EGFR signaling cascade molecules. Indeed, we examined the importance of analyzing the anti-EGFR antibody–drug conjugates (ADC) developed to overcome resistance and/or stimulate the tumor host’s immunity against CRC growth. Also, patient-derived CRC organoid cultures represent a useful and feasible in vitro model to study tumor behavior and therapy response. Organoids can reflect tumor genetic heterogeneity found in the tissue of origin, representing a unique tool for personalized medicine. Thus, CRC-derived organoid cultures are a smart model for studying the tumor microenvironment and for the preclinical assay of anti-EGFR drugs.

Fibroblasts are incredible cells

Understanding the immune landscape of pediatric brain tumors is essential for developing effective immunotherapies. Chen et al. profiled medulloblastoma (MB) subgroups WNT, SHH, Group 3, and Group 4 revealing distinct immune cell infiltration patterns. Group 3 tumors showed elevated CD8+ T cells, Tregs, and endothelial cells. Three hub genes (GAB1, CXCR4, ABL1) were identified as potential biomarkers linked to immune checkpoint responsiveness and drug sensitivity, supporting subgroup-specific immunotherapy strategies. Bhargav et al. highlighted the importance of modeling the pediatric brain tumor microenvironment to improve translational relevance. Their review outlines advanced platforms organoids, organotypic brain slices, and 3D bioengineered systems that better replicate immune-tumor interactions. These models are essential for evaluating immunotherapies and overcoming barriers in MB and glioma. b) CAR-T Cell Therapy: Overcoming Trafficking and Persistence Barriers CAR-T cell therapy holds promise for pediatric brain malignancies but faces significant challenges. Yaacoub et al. reviewed two major obstacles: poor trafficking across the blood-brain barrier (BBB) and limited persistence in the immunosuppressive tumor microenvironment. They discussed locoregional delivery methods, focused ultrasound, and biomaterials to enhance trafficking, alongside CAR engineering strategies co-stimulatory domains, cytokine support, and checkpoint inhibition to improve persistence and efficacy. Cross This Research Topic brings together diverse yet interconnected strategies aimed at improving the effectiveness of immunotherapies in pediatric brain cancer. From molecular profiling and preclinical modeling to CAR-T engineering and neoantigen targeting, the contributions reflect a maturing field that is increasingly data-driven, mechanistically informed, and clinically ambitious. The collective insights emphasize the importance of tailoring immunotherapy to the unique biology of pediatric brain tumors, leveraging subgroup-specific vulnerabilities, and overcoming the structural and immunological barriers of the CNS. Continued innovation in delivery methods, cell engineering, and model systems will be essential to translate these advances into durable clinical benefit.