The tumor microenvironment (TME) plays a crucial role in cancer progression and treatment response, as evidenced by various studies exploring immune interactions within this context. Kirschenbaum et al. introduced Zman-seq, a novel single-cell transcriptomic technology that captures the dynamics of immune cell states over time in glioblastoma, revealing critical immune trajectories that could inform therapeutic strategies (ref: Kirschenbaum doi.org/10.1016/j.cell.2023.11.032/). Heiser et al. employed spatial multi-omic data from colorectal cancer specimens to map tumor evolution, highlighting the individualized progression trajectories and microenvironmental changes that accompany tumor development (ref: Heiser doi.org/10.1016/j.cell.2023.11.006/). In a different approach, Li et al. identified choroid plexus mast cells as key drivers of tumor-associated hydrocephalus, demonstrating their role in increasing cerebrospinal fluid production through the tryptase-PAR2-FoxJ1 pathway, which underscores the importance of mast cells in the TME (ref: Li doi.org/10.1016/j.cell.2023.11.001/). Further investigations into immune cell therapies revealed that Kaczanowska et al. conducted a Phase I trial of GD2 CAR-T cells in solid tumors, identifying factors that influence CAR-T expansion and efficacy in patients with osteosarcoma and neuroblastoma (ref: Kaczanowska doi.org/10.1016/j.ccell.2023.11.011/). Agudo et al. discussed the potential of targeting tumor dormancy to prevent relapse, emphasizing the need for clinical translation of dormancy research (ref: Agudo doi.org/10.1038/s41568-023-00642-x/). Lastly, Ramos Zapatero et al. developed a tree-based analysis method to assess drug responses in patient-derived organoids, linking microenvironmental factors to therapeutic outcomes in colorectal cancer (ref: Ramos Zapatero doi.org/10.1016/j.cell.2023.11.005/). Together, these studies illustrate the complex interplay between the TME and immune responses, highlighting potential avenues for therapeutic intervention.

Genomic and molecular profiling has become essential for understanding cancer biology and guiding treatment strategies. Heiser et al. utilized spatial multi-omic data to perform phylogeographic mapping of colorectal tumors, revealing individualized genetic alterations and their association with microenvironmental changes during tumor progression (ref: Heiser doi.org/10.1016/j.cell.2023.11.006/). This study complements the findings of Chang et al., who investigated genomic alterations in esophageal squamous cell carcinoma, identifying critical copy number alterations and mutations that drive the transition from precancerous lesions to cancer (ref: Chang doi.org/10.1016/j.ccell.2023.11.003/). Furthermore, Chen et al. explored the metabolic regulation of homologous recombination repair, demonstrating that lactylation of MRE11 enhances DNA repair processes, which is crucial for maintaining genomic stability (ref: Chen doi.org/10.1016/j.cell.2023.11.022/). In the context of targeted therapies, Caswell et al. examined the role of the APOBEC3B enzyme in lung cancer evolution and therapy resistance, finding that its upregulation is linked to treatment-induced activation of NF-κB (ref: Caswell doi.org/10.1038/s41588-023-01592-8/). Additionally, Brahma et al. investigated the BAF chromatin remodeler, revealing its synergistic role with RNA polymerase II in regulating chromatin accessibility, which is vital for transcriptional regulation (ref: Brahma doi.org/10.1038/s41588-023-01603-8/). These studies collectively underscore the importance of genomic profiling in elucidating cancer mechanisms and informing therapeutic approaches, while also highlighting the complexities of tumor evolution and resistance mechanisms.

Targeted therapies have shown promise in improving outcomes for various cancer types, as demonstrated by several recent studies. Moore et al. reported on the efficacy of mirvetuximab soravtansine, an antibody-drug conjugate targeting folate receptor α, in platinum-resistant ovarian cancer, achieving an objective response rate of 42.3% compared to 15.9% in the chemotherapy group (ref: Moore doi.org/10.1056/NEJMoa2309169/). Similarly, Sonneveld et al. found that the combination of daratumumab with bortezomib, lenalidomide, and dexamethasone reduced the risk of disease progression or death in multiple myeloma patients, highlighting the effectiveness of combination therapies (ref: Sonneveld doi.org/10.1056/NEJMoa2312054/). In pediatric oncology, Audinot et al. demonstrated that ctDNA quantification significantly improves risk estimation for high-grade osteosarcoma, establishing it as a major prognostic factor independent of clinical parameters (ref: Audinot doi.org/10.1016/j.annonc.2023.12.006/). In breast cancer, Spring et al. reported a 30% pCR rate with sacituzumab govitecan in localized triple-negative breast cancer, indicating its potential as a neoadjuvant therapy (ref: Spring doi.org/10.1016/j.annonc.2023.11.018/). Furthermore, Goetz et al. and Damodaran et al. explored the efficacy of lasofoxifene in ER+/HER2- metastatic breast cancer, showing promising results in overcoming endocrine resistance (ref: Goetz doi.org/10.1016/j.annonc.2023.09.3104/; Damodaran doi.org/10.1016/j.annonc.2023.09.3103/). These findings collectively emphasize the evolving landscape of targeted therapies and their potential to improve patient outcomes across various cancer types.

Clinical trials play a pivotal role in advancing cancer treatment and understanding patient outcomes. Koschmann et al. presented a roadmap for treating pediatric diffuse midline gliomas, identifying barriers such as the need for improved experimental models and enhanced collaboration among stakeholders to facilitate research translation (ref: Koschmann doi.org/10.1016/j.ccell.2023.11.002/). In a phase 1b/2 trial, Taniguchi et al. evaluated the safety and efficacy of stereotactic body radiotherapy with or without a selective dismutase mimetic in pancreatic adenocarcinoma, reporting various adverse events and emphasizing the need for careful patient monitoring (ref: Taniguchi doi.org/10.1016/S1470-2045(23)00478-3/). Monk et al. conducted a randomized trial comparing durvalumab with placebo in locally advanced cervical cancer, revealing treatment-related deaths and adverse events that underscore the complexities of managing such patients (ref: Monk doi.org/10.1016/S1470-2045(23)00479-5/). The IMvigor130 study, reported by Grande et al., demonstrated significant progression-free survival benefits with atezolizumab plus chemotherapy in advanced urothelial carcinoma, although overall survival benefits were not statistically significant (ref: Grande doi.org/10.1016/S1470-2045(23)00540-5/; Bamias et al. doi.org/10.1016/S1470-2045(23)00539-9/). These studies highlight the importance of clinical trials in evaluating new therapies and understanding their impact on patient outcomes, while also addressing the challenges faced in translating findings into clinical practice.

Understanding the biology of cancer and mechanisms of resistance is critical for developing effective therapies. He et al. introduced SEVtras, an algorithm that utilizes single-cell RNA sequencing to delineate small extracellular vesicles (sEVs) and their secretion activity, providing insights into cellular behaviors that influence tumor progression (ref: He doi.org/10.1038/s41592-023-02117-1/). Leeman-Neill et al. conducted whole-genome sequencing of B cell lymphoma, identifying noncoding mutations that lead to super-enhancer retargeting and dysregulation of protein synthesis during lymphoma progression, thereby elucidating potential therapeutic targets (ref: Leeman-Neill doi.org/10.1038/s41588-023-01561-1/). Caswell et al. explored the role of APOBEC3B in lung cancer, revealing its upregulation in response to EGFR-targeted therapy and its contribution to therapy resistance through NF-κB activation (ref: Caswell doi.org/10.1038/s41588-023-01592-8/). Brahma et al. investigated the BAF chromatin remodeler, demonstrating its role in nucleosome eviction and chromatin accessibility, which are essential for transcriptional regulation and cancer cell behavior (ref: Brahma doi.org/10.1038/s41588-023-01603-8/). Zhu et al. highlighted the gut microbiome's influence on multiple myeloma treatment resistance, suggesting that targeting microbial nitrogen recycling could improve therapeutic outcomes (ref: Zhu doi.org/10.1016/j.cmet.2023.11.019/). Collectively, these studies underscore the intricate mechanisms underlying cancer biology and resistance, paving the way for novel therapeutic strategies.

Epidemiological studies provide valuable insights into cancer prevalence, risk factors, and outcomes. Dixon et al. assessed the prevalence of prediabetes among adult survivors of childhood cancer, finding a significant association with increased risks of cardiovascular events and chronic kidney disease, highlighting the need for targeted health interventions in this population (ref: Dixon doi.org/10.1200/JCO.23.01005/). Timmins et al. conducted a pooled analysis of leisure-time physical activity and its association with premenopausal breast cancer, revealing that physical activity may play a protective role, although the evidence is less clear compared to postmenopausal breast cancer (ref: Timmins doi.org/10.1200/JCO.23.01101/). Kjaer et al. investigated the cumulative incidence of second primary cancers in Danish cancer survivors, identifying high-risk groups and emphasizing the importance of long-term monitoring (ref: Kjaer doi.org/10.1016/S1470-2045(23)00538-7/). Li et al. explored the efficacy of neoadjuvant chemo-immunotherapy for locally advanced cervical cancer, demonstrating promising antitumor activity and manageable adverse effects (ref: Li doi.org/10.1016/S1470-2045(23)00531-4/). Rashid et al. reported trends in cancer mortality across England, revealing correlations between cancer mortality and district-level poverty, which underscores the impact of socioeconomic factors on health outcomes (ref: Rashid doi.org/10.1016/S1470-2045(23)00530-2/). These findings highlight the importance of public health initiatives in cancer prevention and management, particularly for vulnerable populations.

Innovative methodologies in cancer research are essential for advancing our understanding and treatment of cancer. Retzer et al. introduced the REP-EQUITY toolkit, which provides a framework for ensuring representative and equitable sample selection in health research, thereby enhancing the generalizability of findings (ref: Retzer doi.org/10.1038/s41591-023-02665-1/). Jagsi et al. reported on the omission of radiotherapy after breast-conserving surgery in selected patients, demonstrating that a subset of patients can achieve excellent survival outcomes without adjuvant radiotherapy, which could reshape treatment protocols (ref: Jagsi doi.org/10.1200/JCO.23.02270/). DeGrave et al. developed a framework for auditing medical-image classifiers using generative AI, which enhances the interpretability of machine learning models in medical contexts, thereby improving trust and understanding among clinicians (ref: DeGrave doi.org/10.1038/s41551-023-01160-9/). Barnabas et al. evaluated the durability of single-dose HPV vaccination, showing high efficacy in preventing persistent HPV infections, which could inform vaccination strategies (ref: Barnabas doi.org/10.1038/s41591-023-02658-0/). Lastly, Fizazi et al. investigated the combination of talazoparib and enzalutamide in metastatic castration-resistant prostate cancer, providing insights into novel treatment strategies that target multiple pathways (ref: Fizazi doi.org/10.1038/s41591-023-02704-x/). These innovations highlight the ongoing evolution of research methodologies that enhance our ability to tackle complex cancer challenges.