The tumor microenvironment (TME) plays a critical role in cancer progression and therapeutic resistance. Recent studies have highlighted the complex interactions between tumor cells and their surrounding stroma, particularly focusing on the role of cancer-associated fibroblasts (CAFs) and immune cells. For instance, Zhang et al. demonstrated that macropinocytosis in CAFs is essential for maintaining their identity under metabolic stress, specifically glutamine deficiency, which is common in pancreatic ductal adenocarcinoma (PDAC). This process helps prevent inflammatory reprogramming, thereby supporting tumor growth and altering the tumor stroma (ref: Zhang doi.org/10.1016/j.ccell.2025.06.021/). In another study, Chen et al. utilized integrated single-cell and spatial transcriptomics to uncover distinct cellular subtypes involved in neural invasion in pancreatic cancer, revealing that tertiary lymphoid structures are abundant in low-neural invasion tumor tissues (ref: Chen doi.org/10.1016/j.ccell.2025.06.020/). These findings underscore the importance of the TME in influencing tumor behavior and highlight potential therapeutic targets within this environment. Moreover, the immune landscape within the TME is significantly affected by genetic alterations in tumor cells. Mahat et al. explored how mutant p53 enhances the expression of immunosuppressive chemokines, thereby impairing the efficacy of immune checkpoint inhibitors in PDAC (ref: Mahat doi.org/10.1016/j.immuni.2025.06.005/). This suggests that the genetic makeup of tumors can dictate the immune response and therapeutic outcomes. Additionally, the study by He et al. on dormant cancer cells revealed that chemotherapy can reactivate these cells, leading to metastatic relapse, which emphasizes the dynamic nature of the TME and its role in cancer recurrence (ref: He doi.org/10.1016/j.ccell.2025.06.007/). Collectively, these studies illustrate the multifaceted interactions within the TME and their implications for cancer treatment strategies.

The interplay between the immune system and cancer cells is a critical area of research, particularly in understanding how tumors evade immune detection and promote their own survival. Recent findings have highlighted various mechanisms through which tumor cells manipulate immune responses. For instance, Liu et al. identified that LARP4-mediated hypertranslation in T cells leads to dysfunction within the tumor microenvironment, suggesting that exhausted T cells undergo significant translational remodeling that impairs their effectiveness (ref: Liu doi.org/10.1038/s41590-025-02232-5/). This highlights the importance of translational control in T cell function and the potential for targeting these pathways to enhance immunotherapy outcomes. Additionally, the study by Pandey et al. demonstrated that Gasdermin C cleavage by Cathepsin S in intestinal epithelial cells amplifies anti-helminth immunity, indicating a novel role for gasdermins beyond their traditional function in cell death (ref: Pandey doi.org/10.1016/j.immuni.2025.06.018/). This finding opens new avenues for understanding immune responses in the context of cancer and other diseases. Furthermore, Qin et al. explored the expression patterns of CC chemokine receptor 7 in hepatocellular carcinoma, revealing that high levels of CCR7 correlate with poorer overall survival, thus providing insights into how immune signaling can influence cancer prognosis (ref: Qin doi.org/10.1038/s41392-025-02308-6/). These studies collectively underscore the complexity of immune interactions in cancer and the need for innovative approaches to harness the immune system for therapeutic benefit.

Metabolic reprogramming is a hallmark of cancer that facilitates tumor growth and survival in hostile environments. Recent research has focused on how tumors adapt their metabolism to support aggressive behaviors and evade therapeutic interventions. For example, Pereira-Martins et al. identified high mitochondrial DNA content as a marker for oxidative phosphorylation-driven acute myeloid leukemias, suggesting a potential therapeutic vulnerability that could be exploited (ref: Pereira-Martins doi.org/10.1038/s41392-025-02303-x/). This highlights the importance of mitochondrial function in cancer metabolism and its implications for treatment strategies. Moreover, the study by Li et al. demonstrated that glutamine synthesis by CAFs promotes the polarization of pro-tumor macrophages, thereby enhancing tumor growth and creating an immunosuppressive microenvironment (ref: Li doi.org/10.1084/jem.20241426/). This finding emphasizes the role of metabolic interactions between tumor cells and the stroma in shaping the tumor microenvironment. Additionally, Zhang et al. showed that macropinocytosis in CAFs is crucial for maintaining their identity under metabolic stress, further illustrating the adaptive mechanisms employed by tumor-associated cells (ref: Zhang doi.org/10.1016/j.ccell.2025.06.021/). Together, these studies reveal the intricate metabolic networks that support tumor progression and highlight potential targets for therapeutic intervention.

Therapeutic resistance remains a significant challenge in cancer treatment, with various mechanisms contributing to the failure of therapies. Recent studies have elucidated several pathways through which tumors evade treatment. Dijkstra et al. investigated subclonal immune evasion in non-small cell lung cancer, revealing that genetically distinct tumor clones can exhibit varying responses to immunotherapy, complicating treatment strategies (ref: Dijkstra doi.org/10.1016/j.ccell.2025.06.012/). This underscores the need for personalized approaches that consider the genetic heterogeneity of tumors. In another study, He et al. demonstrated that chemotherapy can awaken dormant cancer cells, leading to metastatic relapse, which poses a significant hurdle in achieving long-term remission (ref: He doi.org/10.1016/j.ccell.2025.06.007/). This finding highlights the importance of understanding the dynamics of tumor dormancy and the factors that trigger reactivation. Furthermore, Liu et al. revealed that T cell dysfunction in tumors is driven by hypertranslation, suggesting that targeting translational control could enhance the efficacy of adoptive T cell therapies (ref: Liu doi.org/10.1038/s41590-025-02232-5/). Collectively, these studies provide insights into the complex mechanisms of therapeutic resistance and emphasize the need for innovative strategies to overcome these barriers.

Tumor-associated fibroblasts (CAFs) play a pivotal role in the tumor microenvironment, influencing tumor progression and therapeutic responses. Recent research has focused on the metabolic adaptations of CAFs and their impact on tumor behavior. Zhang et al. found that macropinocytosis in CAFs is essential for maintaining their identity under metabolic stress, particularly glutamine deficiency, which is prevalent in pancreatic cancer (ref: Zhang doi.org/10.1016/j.ccell.2025.06.021/). This process helps sustain the myCAF phenotype and prevents inflammatory reprogramming, thereby supporting tumor growth. Additionally, Li et al. demonstrated that glutamine synthesis by CAFs promotes the polarization of pro-tumor macrophages, highlighting the role of CAFs in shaping the immunosuppressive tumor microenvironment (ref: Li doi.org/10.1084/jem.20241426/). This interaction between CAFs and immune cells is crucial for understanding tumor progression and resistance to therapies. Furthermore, the study by Nürnberg et al. emphasized the significance of the microenvironment in cancer cell invasion, revealing how nerve-associated features can influence tumor behavior (ref: Nürnberg doi.org/10.1016/j.ccell.2025.07.004/). Together, these findings underscore the importance of targeting CAFs and their interactions within the stroma as a potential therapeutic strategy.

Cancer stem cells (CSCs) and tumor cell dormancy are critical factors in cancer recurrence and therapeutic resistance. Recent studies have provided insights into the mechanisms underlying dormancy and the characteristics of CSCs. He et al. demonstrated that chemotherapy can induce the awakening of dormant tumor cells, leading to metastatic relapse, which poses a significant challenge in cancer treatment (ref: He doi.org/10.1016/j.ccell.2025.06.007/). This finding highlights the need for strategies that target dormant cells to prevent recurrence. Moreover, Meyer et al. identified a stratification system for breast cancer based on tumor cell phenotypes, revealing high intertumor heterogeneity and the presence of stem-like traits associated with rapid disease recurrence (ref: Meyer doi.org/10.1016/j.ccell.2025.06.019/). This emphasizes the importance of understanding the phenotypic diversity within tumors and its implications for treatment outcomes. Additionally, Liu et al. explored the role of LARP4 in T cell dysfunction, suggesting that hypertranslation may contribute to the exhaustion of T cells within the tumor microenvironment (ref: Liu doi.org/10.1038/s41590-025-02232-5/). Collectively, these studies underscore the significance of CSCs and dormancy in cancer biology and the need for targeted therapies that address these challenges.

The advent of spatial and single-cell transcriptomics has revolutionized our understanding of tumor biology by allowing for detailed mapping of cellular heterogeneity and interactions within the tumor microenvironment. Chen et al. utilized integrated single-cell and spatial transcriptomics to investigate the cellular subtypes involved in neural invasion in pancreatic cancer, revealing distinct lineage dynamics and spatial organization that correlate with tumor behavior (ref: Chen doi.org/10.1016/j.ccell.2025.06.020/). This approach provides valuable insights into the complex interactions between tumor cells and their microenvironment, particularly in the context of neural invasion. Additionally, Meyer et al. employed imaging mass cytometry to characterize the tumor phenotype landscapes of triple-negative breast cancer patients, identifying eleven distinct tumor cell phenotypes associated with disease recurrence (ref: Meyer doi.org/10.1016/j.ccell.2025.06.019/). This highlights the potential of spatial transcriptomics to uncover heterogeneity within tumors and its implications for personalized treatment strategies. Furthermore, the study by Wankhede et al. explored the relationship between tumor immunity status and colorectal cancer risk, emphasizing the importance of immune profiling in understanding cancer progression (ref: Wankhede doi.org/10.1200/JCO-25-00148/). Together, these studies illustrate the transformative impact of spatial and single-cell transcriptomics on cancer research and the potential for these technologies to inform therapeutic decisions.

Targeted and combination therapies are at the forefront of cancer treatment, aiming to improve outcomes by addressing the complexities of tumor biology. Shen et al. conducted a phase 2 trial evaluating genetic subtype-guided immunochemotherapy in relapsed or refractory diffuse large B-cell lymphoma, demonstrating the potential for personalized treatment approaches based on tumor genetics (ref: Shen doi.org/10.1038/s41392-025-02316-6/). This study highlights the importance of tailoring therapies to individual patient profiles to enhance efficacy. Moreover, Qin et al. investigated the expression of CC chemokine receptor 7 in hepatocellular carcinoma, finding that high CCR7 levels are associated with poorer overall survival, suggesting that targeting this pathway could improve treatment responses (ref: Qin doi.org/10.1038/s41392-025-02308-6/). Additionally, the study by Wankhede et al. examined the impact of tumor immunity status on colorectal cancer risk and survival, emphasizing the need for combination therapies that consider both tumor biology and the immune landscape (ref: Wankhede doi.org/10.1200/JCO-25-00148/). Collectively, these findings underscore the potential of targeted and combination therapies to address the challenges of cancer treatment and improve patient outcomes.