The intersection of radiogenomics and personalized radiotherapy has become increasingly significant in understanding treatment resistance and optimizing therapeutic strategies. A study by Shao et al. highlights how radiotherapy-resistant prostate cancer cells evade immune checkpoint blockade through mechanisms involving the senescence-related ataxia telangiectasia and Rad3-related protein, indicating that intrinsic resistance is linked to limited antigen presentation in heterogeneous tumor populations (ref: Shao doi.org/10.1002/cac2.12636/). Similarly, research by Papargyriou et al. demonstrates that branched organoid models of pancreatic ductal adenocarcinoma can recapitulate the intratumoral heterogeneity that contributes to chemoresistance, emphasizing the need for models that reflect the complex tumor microenvironment to better predict treatment responses (ref: Papargyriou doi.org/10.1038/s41551-024-01273-9/). Furthermore, Passiglia et al. report on the European Program for the Routine Testing of Patients With Advanced Lung Cancer (EPROPA), which identified numerous actionable mutations in non-small cell lung cancer (NSCLC) samples, underscoring the importance of comprehensive genomic profiling in enhancing patient access to targeted therapies and clinical trials (ref: Passiglia doi.org/10.1016/j.jtho.2024.12.010/). These findings collectively highlight the critical role of genomic profiling in tailoring radiotherapy and improving patient outcomes across various cancer types.

The tumor microenvironment plays a pivotal role in shaping immune responses and treatment efficacy, particularly in the context of immunotherapy. Iltis et al. reveal that senescent cells can evade immune surveillance by upregulating the ganglioside GD3, which suppresses natural killer (NK) cell activity, thus contributing to the accumulation of senescent cells with age (ref: Iltis doi.org/10.1038/s43587-024-00776-z/). This finding is complemented by Go et al., who demonstrate that tissue-resident natural killer cells enhance CD8 T-cell activity in pancreatic cancer, suggesting that localized immune responses can be bolstered by targeting the tumor microenvironment (ref: Go doi.org/10.7554/eLife.92672/). Additionally, Li et al. present a radiotherapy-immunomodulated nanoplatform that generates tumor-associated antigens, promoting a robust abscopal effect and sustained immune memory, thereby addressing the challenges posed by hypoxic tumor microenvironments (ref: Li doi.org/10.1016/j.biomaterials.2024.123005/). These studies collectively underscore the importance of understanding and manipulating the tumor microenvironment to enhance the efficacy of immunotherapeutic strategies.

Understanding the mechanisms underlying radioresistance is crucial for improving therapeutic outcomes in cancer treatment. Research by Brown et al. elucidates how the STING pathway, a key player in mediating antitumor immunity post-radiotherapy, is suppressed by factors such as YTHDF1 and HO-1, leading to diminished immune responses (ref: Brown doi.org/10.1172/JCI186547/). Zhang et al. further investigate the role of HO-1 in impairing radiotherapy efficacy by redistributing cGAS and STING in tumors, thereby disrupting the production of type I interferons critical for effective radiotherapy (ref: Zhang doi.org/10.1172/JCI181044/). Additionally, Hu et al. identify GPR37 as a significant factor in enhancing radiosensitivity in esophageal squamous cell carcinoma, suggesting that targeting specific molecular pathways may offer new strategies to overcome radioresistance (ref: Hu doi.org/10.1038/s41419-024-07240-1/). These findings highlight the multifaceted nature of radioresistance and the potential for targeted interventions to improve radiotherapy outcomes.

Innovative therapeutic strategies are emerging to enhance treatment efficacy and address challenges in cancer therapy. Lee et al. introduce shape-morphing, implantable 3D microLEDs that enable continuous light irradiation for metronomic photodynamic therapy in pancreatic cancer, demonstrating a novel approach to improve drug activation within the tumor microenvironment (ref: Lee doi.org/10.1002/adma.202411494/). Xu et al. explore the use of an NIR-II two-photon excitable photosensitizer for precise treatment of small glioblastoma tumors, highlighting the potential of advanced photodynamic therapy techniques to address residual tumor challenges post-surgery (ref: Xu doi.org/10.1002/adma.202413164/). Furthermore, Wang et al. present a logic-gated PANoptosis strategy for osteosarcoma treatment, combining immunotherapy with localized cell death pathways to enhance therapeutic specificity and reduce side effects (ref: Wang doi.org/10.1002/adma.202415814/). These innovative approaches reflect a shift towards more personalized and effective cancer therapies that leverage technological advancements.

Genomic profiling and the identification of biomarkers are critical for advancing personalized medicine in oncology. Passiglia et al. emphasize the importance of comprehensive genomic profiling in identifying actionable mutations in NSCLC, which facilitates patient enrollment in targeted clinical trials and enhances treatment outcomes (ref: Passiglia doi.org/10.1016/j.jtho.2024.12.010/). He et al. investigate the role of N-terminal acetylation of the transcription factor LIP in mediating immune therapy resistance through the suppression of PD-L1 expression in NSCLC, revealing potential biomarkers for predicting treatment responses (ref: He doi.org/10.1136/jitc-2024-009905/). Additionally, Cui et al. demonstrate that targeting arachidonic acid metabolism can enhance immunotherapy efficacy in ARID1A-deficient colorectal cancer, suggesting that metabolic pathways may serve as novel biomarkers for therapeutic response (ref: Cui doi.org/10.1158/0008-5472.CAN-24-1611/). Collectively, these studies underscore the transformative potential of genomic profiling and biomarker identification in tailoring cancer therapies.

Clinical outcomes and treatment efficacy remain central to evaluating cancer therapies. Lin et al. report that patients with EGFR-mutant NSCLC treated with osimertinib experienced a higher incidence of cardiac events compared to those on other EGFR TKIs, with significant implications for overall survival (ref: Lin doi.org/10.1001/jamanetworkopen.2024.48364/). Wenzel et al. explore the genomic profiles of patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing radioligand therapy, revealing disparities in progression-free survival and overall survival based on genetic mutations (ref: Wenzel doi.org/10.1200/PO-24-00645/). Furthermore, Riviere-Cazaux et al. present a novel method for longitudinal glioma monitoring via cerebrospinal fluid cell-free DNA, which could enhance response assessment and treatment personalization (ref: Riviere-Cazaux doi.org/10.1158/1078-0432.CCR-24-1814/). These findings highlight the importance of integrating clinical outcomes with genomic insights to refine treatment strategies.

Advancements in radiation therapy techniques are crucial for improving treatment precision and patient outcomes. The American College of Medical Genetics and Genomics provides guidelines for managing individuals with heterozygous germline pathogenic variants in ATM, emphasizing the need for tailored approaches in radiation therapy (ref: Pal doi.org/10.1016/j.gim.2024.101243/). Lee et al. also discuss the Pan-Asian adapted ESMO guidelines for managing oncogene-addicted metastatic NSCLC, which highlight regional disparities in treatment access and efficacy (ref: Lee doi.org/10.1016/j.esmoop.2024.103996/). Additionally, Brown et al. address the role of the STING pathway in mediating radiation resistance, suggesting that targeting this pathway could enhance the efficacy of radiotherapy (ref: Brown doi.org/10.1172/JCI186547/). These innovations reflect a concerted effort to refine radiation therapy techniques and improve patient care.