The tumor microenvironment (TME) plays a critical role in modulating immune responses and tumor progression. Recent studies have highlighted the interplay between genetic mutations and immune cell interactions within the TME. For instance, Leca et al. developed a mouse model of angioimmunoblastic T-cell lymphoma (AITL) driven by IDH2 and TET2 mutations, revealing how these mutations influence T follicular helper (Tfh) cell interactions with the AITL microenvironment (ref: Leca doi.org/10.1016/j.ccell.2023.01.003/). In another study, Gong et al. demonstrated that lung mesenchymal cells can reprogram neutrophils to adopt an immunosuppressive phenotype, thereby promoting breast cancer metastasis, indicating that the TME can significantly alter the functional state of immune cells (ref: Gong doi.org/10.1126/sciimmunol.add5204/). Furthermore, Yang et al. explored the potential of toosendanin, a small-molecule compound, to reverse macrophage-mediated immunosuppression in glioblastoma, suggesting that targeting TME components may enhance the efficacy of immunotherapies (ref: Yang doi.org/10.1126/scitranslmed.abq3558/). These findings collectively underscore the importance of understanding the TME's role in shaping immune responses and tumor behavior, paving the way for novel therapeutic strategies that target these interactions. In addition to immune cell modulation, the TME's biochemical landscape is crucial for tumor progression. Faraoni et al. investigated the role of CD73-dependent adenosine signaling in ductal pancreatic cancer, revealing how this pathway contributes to the immunosuppressive environment characteristic of pancreatic tumors (ref: Faraoni doi.org/10.1158/0008-5472.CAN-22-2553/). Similarly, Sánchez-Magraner et al. found that functional engagement of the PD-1/PD-L1 complex, rather than mere expression levels, is a strong predictor of patient response to immunotherapy in non-small-cell lung cancer, highlighting the need for precise biomarkers to guide treatment decisions (ref: Sánchez-Magraner doi.org/10.1200/JCO.22.01748/). Overall, these studies illustrate the complex dynamics of the TME and its significant implications for cancer immunotherapy and patient outcomes.

Metabolic reprogramming is increasingly recognized as a hallmark of cancer, influencing tumor growth, resistance to therapy, and the tumor microenvironment. Zhang et al. demonstrated that phosphoglycerate dehydrogenase (PHGDH) in endothelial cells contributes to glioblastoma resistance to CAR-T cell immunotherapy by creating a hypoxic and immune-hostile vascular environment (ref: Zhang doi.org/10.1016/j.cmet.2023.01.010/). This finding emphasizes the role of endothelial metabolism in shaping the tumor's response to immunotherapy. In a related study, Altea-Manzano et al. identified that a palmitate-rich metastatic niche enhances metastasis growth through p65 acetylation, which activates pro-metastatic NF-κB signaling, suggesting that specific nutrients in the tumor microenvironment can promote aggressive cancer behavior (ref: Altea-Manzano doi.org/10.1038/s43018-023-00513-2/). Moreover, Liu et al. introduced a hypoxia-activated prodrug that targets hypoxic cancer cells, showcasing a novel approach to exploit the unique metabolic characteristics of tumors for therapeutic gain (ref: Liu doi.org/10.1002/adma.202210363/). The study by Cheng et al. on single-atom nanocatalysts further highlights the potential of nanotechnology in enhancing therapeutic efficacy through metabolic modulation (ref: Cheng doi.org/10.1002/adma.202210037/). Additionally, Linares et al. reported that long-term accumulation of platinum-based drugs in cancer-associated fibroblasts contributes to colorectal cancer progression and therapy resistance, indicating that metabolic interactions between tumor cells and the stroma are critical for treatment outcomes (ref: Linares doi.org/10.1038/s41467-023-36334-1/). Collectively, these studies underscore the intricate relationship between metabolic reprogramming and cancer progression, suggesting that targeting metabolic pathways may offer new avenues for therapeutic intervention.

The extracellular matrix (ECM) is a dynamic component of the tumor microenvironment that significantly influences tumor growth and progression. Wu et al. found that a stiff ECM promotes exosome secretion from cancer cells, which in turn enhances tumor growth through activation of the Notch signaling pathway (ref: Wu doi.org/10.1038/s41556-023-01092-1/). This study highlights the mechanical properties of the ECM as a critical factor in tumor biology, suggesting that targeting ECM stiffness may be a viable therapeutic strategy. In another investigation, Jiang et al. explored how bacterial enzymes can modify protein post-translational modifications in host cells, revealing a novel mechanism by which the gut microbiome can influence tumorigenesis through ECM interactions (ref: Jiang doi.org/10.1136/gutjnl-2022-327853/). Kemna et al. examined the role of interferon-gamma (IFN-γ) binding to the ECM in preventing systemic toxicity, indicating that ECM interactions can modulate immune responses and cytokine activity (ref: Kemna doi.org/10.1038/s41590-023-01420-5/). Furthermore, Ross et al. demonstrated that nanotopography can regulate the immunomodulatory phenotype of mesenchymal stromal cells (MSCs) by altering their metabolic state, suggesting that ECM properties can directly influence cellular behavior and immune modulation (ref: Ross doi.org/10.1038/s41467-023-36293-7/). Lastly, Xun et al. developed a method to reconstruct the spatial microenvironment of tumors, allowing for a better understanding of cellular interactions at the tumor boundary (ref: Xun doi.org/10.1038/s41467-023-36560-7/). These findings collectively emphasize the importance of the ECM in tumor biology and its potential as a target for therapeutic interventions.

Cancer immunotherapy has revolutionized treatment paradigms, yet resistance mechanisms remain a significant challenge. Yang et al. investigated the potential of toosendanin to reverse macrophage-mediated immunosuppression in glioblastoma, demonstrating its ability to enhance T cell responses and overcome resistance to immunotherapy (ref: Yang doi.org/10.1126/scitranslmed.abq3558/). This study highlights the importance of targeting the immune suppressive components of the tumor microenvironment to improve therapeutic outcomes. Biondi et al. focused on the selective homing of CAR-CIK cells to the bone marrow niche in acute myeloid leukemia, revealing that enhancing the accumulation of these cells in the leukemia microenvironment can improve treatment efficacy (ref: Biondi doi.org/10.1182/blood.2022018330/). Li et al. developed genetically programmable vesicles to enhance CAR-T therapy against solid tumors by targeting the immunosuppressive TME, illustrating a novel approach to improve CAR-T cell functionality (ref: Li doi.org/10.1002/adma.202211138/). Additionally, Kwon et al. constructed a single-cell expression atlas to identify optimal target antigens for CAR therapy, addressing the challenge of intratumoral heterogeneity in cancer (ref: Kwon doi.org/10.1038/s41587-023-01686-y/). Yam et al. explored microbial therapy's potential to convert neutrophils into tumor-killing phenotypes, demonstrating that altering the inflammatory state of the TME can enhance therapeutic efficacy (ref: Yam doi.org/10.1158/0008-5472.CAN-21-4025/). These studies collectively underscore the complexity of resistance mechanisms in cancer immunotherapy and the need for innovative strategies to overcome them.

Understanding the cellular and molecular dynamics in tumor progression is crucial for developing effective therapies. Kwon et al. constructed a single-cell expression atlas to dissect the immune suppressive microenvironment in prostate cancer, revealing insights into the interactions between tumor and immune cells that drive disease progression (ref: Kwon doi.org/10.1038/s41587-023-01686-y/). Seike et al. demonstrated that ambient oxygen levels can regulate intestinal dysbiosis and the severity of graft-versus-host disease, highlighting the influence of the microenvironment on immune responses and tumor dynamics (ref: Seike doi.org/10.1016/j.immuni.2023.01.007/). These findings suggest that environmental factors play a significant role in shaping tumor behavior and immune interactions. Sánchez-Magraner et al. emphasized the importance of functional engagement of the PD-1/PD-L1 complex in predicting patient responses to immunotherapy in non-small-cell lung cancer, indicating that molecular interactions within the TME can significantly impact treatment outcomes (ref: Sánchez-Magraner doi.org/10.1200/JCO.22.01748/). He et al. conducted a phase 2 trial of sitravatinib with nivolumab in patients with nonsquamous NSCLC, demonstrating that targeting multiple pathways can shift the TME toward an immunostimulatory state, although the overall response rate was modest (ref: He doi.org/10.1016/j.jtho.2023.02.016/). Zou et al. uncovered a neurodevelopmental epigenetic program that promotes medulloblastoma metastasis, illustrating how molecular pathways can be hijacked to facilitate tumor progression (ref: Zou doi.org/10.1038/s41556-023-01093-0/). Collectively, these studies highlight the intricate interplay between cellular dynamics, molecular pathways, and the tumor microenvironment in cancer progression.

Tumor-associated fibroblasts (TAFs) play a pivotal role in cancer progression and therapy resistance. Linares et al. demonstrated that long-term accumulation of platinum-based drugs in cancer-associated fibroblasts (CAFs) contributes to colorectal cancer progression and resistance to therapy, suggesting that targeting CAFs may enhance treatment efficacy (ref: Linares doi.org/10.1038/s41467-023-36334-1/). Li et al. identified macrophages as key players in promoting anti-androgen resistance in metastatic castration-resistant prostate cancer, indicating that the metastatic microenvironment significantly influences treatment outcomes (ref: Li doi.org/10.1084/jem.20221007/). These findings underscore the importance of understanding the interactions between TAFs and tumor cells in developing effective therapeutic strategies. Ryan et al. explored how NRF2 activation can restore macrophage function in chronic obstructive pulmonary disease, highlighting the potential of targeting metabolic pathways in TAFs to improve immune responses in the tumor microenvironment (ref: Ryan doi.org/10.1164/rccm.202203-0482OC/). Collectively, these studies emphasize the critical role of TAFs in shaping the tumor microenvironment and their potential as therapeutic targets in cancer treatment.

Single-cell and spatial transcriptomics are revolutionizing our understanding of tumor heterogeneity and microenvironment interactions. Hirz et al. utilized integrated single-cell and spatial transcriptomic analyses to dissect the immune suppressive microenvironment in prostate cancer, revealing distinct cellular populations that contribute to tumor progression (ref: Hirz doi.org/10.1038/s41467-023-36325-2/). Viswanathan et al. focused on chronic thromboembolic pulmonary hypertension, employing single-cell analysis to identify immune and smooth muscle cell populations involved in disease pathobiology, thus highlighting the utility of single-cell approaches in understanding complex diseases (ref: Viswanathan doi.org/10.1164/rccm.202203-0441OC/). Ren et al. applied spatial transcriptomics to uncover niche-specific vulnerabilities of radial glial stem-like cells in malignant gliomas, demonstrating how spatial context influences tumor cell behavior and therapeutic responses (ref: Ren doi.org/10.1038/s41467-023-36707-6/). These studies collectively illustrate the power of single-cell and spatial transcriptomics in elucidating the cellular dynamics and microenvironmental factors that drive tumor progression, paving the way for more targeted and effective therapeutic strategies.

Nanotechnology is emerging as a transformative approach in cancer therapy, enhancing drug delivery and therapeutic efficacy. Yan et al. introduced planted graphene quantum dots (GQDs) as a novel tool for targeted tumor imaging and long-term visualization of pharmacokinetics, demonstrating their potential in multimodal bioimaging applications (ref: Yan doi.org/10.1002/adma.202210809/). This advancement highlights the importance of nanomaterials in improving the precision of cancer diagnostics and treatment monitoring. Deng et al. explored a biomimetic mineralization method for synthesizing manganese oxide nanoparticles, which can enhance the immunogenicity of radiotherapy-induced cell death, thereby improving systemic antitumor immune responses (ref: Deng doi.org/10.1021/acsnano.2c10352/). Pan et al. developed an upconversion nanomachine for precise near-infrared phototherapy, showcasing the potential of engineered nanoplatforms to deliver targeted therapies in a controlled manner (ref: Pan doi.org/10.1021/acsnano.2c10453/). Jo et al. applied photoacoustic imaging to predict tumor response to therapy based on oxygen distribution, emphasizing the role of nanotechnology in real-time monitoring of therapeutic efficacy (ref: Jo doi.org/10.1021/acsnano.2c09502/). Collectively, these studies underscore the transformative potential of nanotechnology in enhancing cancer therapy through improved targeting, monitoring, and therapeutic outcomes.