The intersection of radiogenomics and personalized radiotherapy has gained significant attention, particularly in understanding the long-term risks faced by childhood cancer survivors. A study by Gibson et al. analyzed data from 11,220 survivors, revealing that cancer-specific polygenic risk scores (PRSs) can predict the likelihood of developing subsequent cancers such as basal cell carcinoma and melanoma, with odds ratios indicating a substantial risk increase (OR = 1.60 for melanoma, 95% CI = 1.31-1.96) (ref: Gibson doi.org/10.1038/s41591-024-02837-7/). This highlights the importance of integrating genetic predisposition into treatment planning to mitigate future cancer risks. In another study, Subramanian et al. utilized a machine-learning framework to characterize the cellular ecosystems within soft tissue sarcomas, identifying 23 sarcoma-specific cell states that correlate with patient prognosis and response to immunotherapy (ref: Subramanian doi.org/10.1038/s43018-024-00743-y/). This approach underscores the potential of personalized therapies tailored to the unique genetic and cellular profiles of tumors. Furthermore, the exploration of threonine's role in glioblastoma by Wu et al. demonstrated how metabolic reprogramming can enhance protein translation in cancer stem cells, suggesting that targeting metabolic pathways may offer new therapeutic avenues (ref: Wu doi.org/10.1038/s43018-024-00748-7/).

Immunotherapy continues to evolve, particularly in addressing challenges posed by tumor microenvironments (TMEs) that facilitate immune evasion. Beck et al. demonstrated that mRNA-encoded interleukin-2 can restore CD8+ T cell infiltration in tumors lacking MHC class I, thereby reversing immune desertification and enhancing responses to combined therapies (ref: Beck doi.org/10.1016/j.ccell.2024.02.013/). This finding emphasizes the potential of using cytokine-based therapies to modify the TME for improved immunotherapeutic outcomes. In a phase Ib trial, Kelly et al. explored the efficacy of neoadjuvant nivolumab alone or in combination with the LAG-3 inhibitor relatlimab in gastroesophageal cancer, revealing promising immune responses and potential synergistic effects (ref: Kelly doi.org/10.1038/s41591-024-02877-z/). Additionally, Kim et al. reported that targeted deletion of CD244 on monocytes can promote differentiation into anti-tumor macrophages, enhancing the efficacy of PD-L1 blockade in melanoma (ref: Kim doi.org/10.1186/s12943-024-01936-w/). These studies collectively highlight the dynamic interplay between immunotherapy and the TME, suggesting that strategies aimed at modifying immune cell populations may significantly improve treatment responses.

Understanding the mechanisms underlying drug resistance is crucial for improving cancer treatment outcomes. Yan et al. identified that suppression of ITPKB degradation by Trim25 contributes to temozolomide resistance in glioblastoma through the maintenance of reactive oxygen species (ROS) homeostasis, indicating a potential target for overcoming resistance (ref: Yan doi.org/10.1038/s41392-024-01763-x/). In parallel, Bi et al. highlighted the role of polyamines in promoting ferroptosis, suggesting that targeting this metabolic pathway could exploit vulnerabilities in cancer cells (ref: Bi doi.org/10.1038/s41467-024-46776-w/). Furthermore, Huang et al. demonstrated that EZH2 inhibition enhances PD-L1 stability in colorectal cancer, which may influence the effectiveness of immune checkpoint inhibitors (ref: Huang doi.org/10.1002/advs.202308045/). These findings point to a multifaceted approach in addressing drug resistance, where both metabolic pathways and immune evasion mechanisms are targeted to enhance therapeutic efficacy. Additionally, the ACTION trial by Arrillaga-Romany et al. evaluated ONC201 in H3 K27M-mutant glioma, providing insights into novel treatment strategies for this challenging malignancy (ref: Arrillaga-Romany doi.org/10.1093/neuonc/).

The genomic and molecular characterization of cancers is pivotal for advancing personalized medicine. Subramanian et al. employed a machine-learning framework to dissect the cellular ecosystems within sarcomas, identifying 23 transcriptionally defined cell states that correlate with patient outcomes and responses to immunotherapy (ref: Subramanian doi.org/10.1038/s43018-024-00743-y/). This approach underscores the potential for tailored therapeutic strategies based on specific tumor microenvironments. Additionally, Li et al. characterized novel molecular subtypes of intracranial germ cell tumors, revealing distinct genomic profiles that could inform treatment decisions (ref: Li doi.org/10.1093/neuonc/). The study by Ma et al. further elucidated the role of microbiota in breast cancer, demonstrating that enterotoxigenic Bacteroides fragilis can enhance chemoresistance, highlighting the need to consider microbial influences in cancer therapy (ref: Ma doi.org/10.1093/procel/). These findings collectively emphasize the importance of integrating genomic data with clinical outcomes to refine therapeutic approaches.

Innovative therapeutic approaches are reshaping cancer treatment paradigms. Friedman et al. investigated the long-term outcomes of risk-based therapy in neuroblastoma survivors, revealing significant differences in late morbidity and mortality based on treatment stratification (ref: Friedman doi.org/10.1093/jnci/). This highlights the importance of personalized treatment strategies that consider long-term effects. Hu et al. introduced a bioinspired immunostimulatory system capable of inducing antitumor immune responses through direct plasma membrane rupture, demonstrating a novel mechanism for cancer cell death (ref: Hu doi.org/10.1002/advs.202305934/). Additionally, the study by Li et al. on CDKL1's role in enhancing the efficacy of radioimmunotherapy in lung cancer underscores the potential of combining targeted therapies with traditional modalities (ref: Li doi.org/10.1186/s13046-024-03007-w/). These innovative approaches reflect a shift towards more effective and less toxic cancer therapies, emphasizing the need for ongoing research into novel treatment modalities.

Ferroptosis, a regulated form of cell death, has emerged as a critical area of study in cancer metabolism. Bi et al. identified arginine as a promoter of ferroptosis through its conversion to polyamines, suggesting that metabolic manipulation could be a viable therapeutic strategy (ref: Bi doi.org/10.1038/s41467-024-46776-w/). In contrast, Chen et al. demonstrated that TRIB3 inhibits ferroptosis in head and neck squamous cell carcinoma, indicating that targeting this pathway could enhance treatment efficacy (ref: Chen doi.org/10.1038/s41419-024-06472-5/). Furthermore, Ma et al. explored the role of microbiota in promoting breast cancer cell stemness and chemoresistance, revealing that enterotoxigenic Bacteroides fragilis can influence tumor metabolism and treatment responses (ref: Ma doi.org/10.1093/procel/). These studies collectively highlight the complex interplay between metabolic pathways and ferroptosis in cancer, suggesting that therapeutic strategies targeting these mechanisms may improve treatment outcomes.

Clinical trials remain essential for evaluating new cancer therapies and understanding treatment outcomes. The phase Ib trial by Kelly et al. assessed the efficacy of neoadjuvant nivolumab and nivolumab plus relatlimab in gastroesophageal cancer, providing insights into the potential for dual checkpoint inhibition to enhance therapeutic responses (ref: Kelly doi.org/10.1038/s41591-024-02877-z/). Additionally, Baker et al. introduced FUME-TCRseq, a novel methodology for T-cell receptor sequencing from degraded RNA, which could significantly improve the analysis of immune responses in clinical samples (ref: Baker doi.org/10.1158/0008-5472.CAN-23-3340/). Furthermore, Wang et al. discussed the activation of ERβ in triple-negative breast cancer, highlighting the need for innovative therapies beyond traditional chemotherapy (ref: Wang doi.org/10.1073/pnas.2306814121/). These findings underscore the importance of ongoing clinical research in refining treatment strategies and improving patient outcomes.

Advancements in radiotherapy techniques are crucial for improving treatment outcomes in cancer patients. The CONVERT trial, as reported by Walls et al., compared once-daily and twice-daily radiation therapy in limited-stage small cell lung cancer, revealing long-term outcomes that could inform treatment protocols (ref: Walls doi.org/10.1016/j.ijrobp.2024.02.063/). Additionally, Gharzai et al. conducted a meta-analysis identifying surrogate endpoints for overall survival in p16-positive oropharyngeal cancers, which could enhance the design of future clinical trials (ref: Gharzai doi.org/10.1016/S1470-2045(24)00016-0/). Moreover, Li et al. developed a novel sonosensitizer for sonodynamic therapy in bladder cancer, demonstrating improved electron-hole separation and therapeutic efficacy (ref: Li doi.org/10.1002/adma.202401252/). These studies collectively emphasize the ongoing evolution of radiotherapy techniques and their potential to improve patient outcomes across various cancer types.