The tumor microenvironment (TME) plays a crucial role in cancer progression and therapy response. Recent studies have highlighted the impact of specific cellular components within the TME, such as natural killer (NK) cells and myeloid cells. For instance, Peng et al. demonstrated that CALHM2-knockout NK cells exhibit enhanced cytotoxicity and tumor infiltration, suggesting potential genetic checkpoints for improving CAR-NK therapy (ref: Peng doi.org/10.1038/s41587-024-02282-4/). In another study, Villa et al. explored the dual role of TREM2 in glioblastoma-associated myeloid cells, revealing its involvement in promoting inflammation at the tumor-neural interface while suppressing it within the tumor core, influenced by the local microenvironment (ref: Villa doi.org/10.1016/j.ccell.2024.05.018/). Furthermore, McGinnis et al. provided insights into the temporal progression of lung immune remodeling during breast cancer metastasis, emphasizing the dynamic changes in immune cell phenotypes and intercellular communication in the metastatic niche (ref: McGinnis doi.org/10.1016/j.ccell.2024.05.004/). These findings underscore the complexity of the TME and its implications for therapeutic strategies. Additionally, the metabolic interactions within the TME have been shown to influence tumor progression and immune evasion. Jiang et al. identified a metabolic "face-off" mechanism between macrophages and fibroblasts in gastric cancer, highlighting the prognostic significance of nicotinamide metabolism (ref: Jiang doi.org/10.1016/j.cmet.2024.05.013/). Tharp et al. and Perricone et al. both addressed the role of tumor-associated macrophages (TAMs) in fibrotic tumors, where TAMs initiate collagen biosynthesis in response to a stiffened TME, creating a metabolic environment that restricts CD8+ T cell activity (ref: Tharp doi.org/10.1038/s43018-024-00775-4/; ref: Perricone doi.org/10.1038/s43018-024-00758-5/). Collectively, these studies illustrate the multifaceted interactions within the TME that dictate tumor behavior and therapeutic outcomes.

The interplay between the immune system and tumor microenvironment is pivotal in shaping cancer progression and treatment responses. Recent research has focused on various immune cell types, particularly natural killer (NK) cells and tumor-associated macrophages (TAMs). Peng et al. highlighted the potential of CALHM2-knockout NK cells to enhance cytotoxicity and tumor infiltration, suggesting that genetic modifications could improve CAR-NK therapy outcomes (ref: Peng doi.org/10.1038/s41587-024-02282-4/). In contrast, the study by Guruprasad et al. revealed that the BTLA-HVEM axis on T cells and regulatory T cells restricts CAR T cell efficacy, indicating that immunosuppressive interactions within the TME can hinder therapeutic effectiveness (ref: Guruprasad doi.org/10.1038/s41590-024-01847-4/). Moreover, Villa et al. explored the spatial diversity of myeloid cell functions in glioblastoma, demonstrating that TREM2 plays a dual role in promoting inflammation and suppression depending on the local microenvironment (ref: Villa doi.org/10.1016/j.ccell.2024.05.018/). This highlights the complexity of immune interactions in tumors, where the same cell type can have opposing effects based on its context. Additionally, Tharp et al. and Perricone et al. discussed how TAMs contribute to immune evasion in fibrotic tumors by creating a metabolic environment that limits CD8+ T cell infiltration (ref: Tharp doi.org/10.1038/s43018-024-00775-4/; ref: Perricone doi.org/10.1038/s43018-024-00758-5/). These findings emphasize the need for therapeutic strategies that can modulate immune interactions within the TME to enhance anti-tumor immunity.

Metabolic reprogramming is a hallmark of cancer that significantly influences tumor growth and immune evasion. Recent studies have elucidated the complex metabolic interactions within the tumor microenvironment, particularly focusing on the roles of nicotinamide metabolism and the metabolic adaptations of tumor-associated fibroblasts and macrophages. Jiang et al. identified a metabolic "face-off" between macrophages and fibroblasts in gastric cancer, revealing that the dynamics of nicotinamide metabolism can serve as a dual prognostic marker for patient outcomes (ref: Jiang doi.org/10.1016/j.cmet.2024.05.013/). This highlights the multifactorial nature of metabolic interactions that can influence the efficacy of immune checkpoint blockade therapies. Moreover, Zhou et al. developed HRS-4642, a selective KRAS G12D inhibitor, demonstrating robust anti-tumor efficacy against KRAS G12D-mutant cancers both in vitro and in vivo (ref: Zhou doi.org/10.1016/j.ccell.2024.06.001/). This study underscores the importance of targeting specific metabolic pathways in cancer therapy. Additionally, the work by Tharp et al. and Perricone et al. emphasized how fibrotic tumors can tune their metabolism to evade immune detection, suggesting that targeting the metabolic pathways associated with fibrosis could reawaken anti-tumor immunity (ref: Tharp doi.org/10.1038/s43018-024-00775-4/; ref: Perricone doi.org/10.1038/s43018-024-00758-5/). Collectively, these studies illustrate the critical role of metabolic reprogramming in shaping tumor behavior and therapeutic responses.

Innovative therapeutic strategies targeting the tumor microenvironment (TME) are emerging as promising approaches to enhance cancer treatment efficacy. Recent studies have focused on various modalities, including targeted therapies, immune checkpoint inhibitors, and engineered scaffolds. Zhou et al. introduced HRS-4642, a selective KRAS G12D inhibitor, which exhibited significant anti-tumor efficacy in preclinical models, highlighting the potential of targeted therapies in overcoming the challenges posed by specific oncogenic mutations (ref: Zhou doi.org/10.1016/j.ccell.2024.06.001/). Furthermore, Zhao et al. investigated the combination of fibroblast activation protein (FAP)-targeted radioligand therapy with immune checkpoint blockade, demonstrating synergistic effects that enhance tumor uptake and retention of therapeutic agents (ref: Zhao doi.org/10.1038/s41392-024-01853-w/). In addition, Zhang et al. reported on the use of biodegradable scaffolds to restimulate the antitumor activity of pre-administered CAR-T cells, showing that these scaffolds can create a microenvironment conducive to T cell activation and persistence (ref: Zhang doi.org/10.1038/s41551-024-01216-4/). This approach underscores the importance of engineering the TME to support effective immunotherapy. Moreover, the studies by Tharp et al. and Perricone et al. highlighted the role of TAMs and fibrotic components in the TME, suggesting that targeting these elements could enhance the efficacy of existing therapies (ref: Tharp doi.org/10.1038/s43018-024-00775-4/; ref: Perricone doi.org/10.1038/s43018-024-00758-5/). Overall, these findings illustrate the potential of innovative therapeutic strategies that leverage the TME to improve cancer treatment outcomes.

Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the tumor microenvironment and influencing cancer progression. Recent studies have focused on the interactions between CAFs and other stromal components, particularly in the context of immune evasion and metabolic reprogramming. Jiang et al. highlighted a metabolic "face-off" between macrophages and fibroblasts in gastric cancer, revealing that the interplay of nicotinamide metabolism can significantly impact tumor behavior and patient prognosis (ref: Jiang doi.org/10.1016/j.cmet.2024.05.013/). This study emphasizes the complexity of metabolic interactions within the TME and their implications for therapeutic strategies. Additionally, Tharp et al. and Perricone et al. discussed how fibrotic tumors, characterized by excessive extracellular matrix deposition and inflammation, can create a hostile environment for immune cells, particularly CD8+ T cells (ref: Tharp doi.org/10.1038/s43018-024-00775-4/; ref: Perricone doi.org/10.1038/s43018-024-00758-5/). These findings suggest that targeting the fibrotic components of the TME may provide therapeutic opportunities to enhance anti-tumor immunity. Furthermore, Zhang et al. explored the use of biodegradable scaffolds to enhance CAR-T cell activity by creating a supportive microenvironment for T cell expansion and differentiation (ref: Zhang doi.org/10.1038/s41551-024-01216-4/). Collectively, these studies underscore the critical role of CAFs and stromal interactions in modulating the TME and their potential as therapeutic targets in cancer treatment.

Understanding the spatial and temporal dynamics of tumor microenvironments is essential for elucidating the mechanisms of cancer progression and therapy response. Recent advancements in spatial transcriptomics have enabled high-resolution analysis of tissue architecture and cellular interactions within tumors. Schott et al. introduced Open-ST, an open-source platform for high-resolution spatial transcriptomics, facilitating the study of molecular organization in 2D and 3D contexts (ref: Schott doi.org/10.1016/j.cell.2024.05.055/). This innovative approach allows researchers to investigate the spatial distribution of various cell types and their functional states within the TME. Moreover, Villa et al. examined the spatial diversity of myeloid cell functions in glioblastoma, revealing the dual role of TREM2 in promoting inflammation at the tumor-neural interface while suppressing it within the tumor core (ref: Villa doi.org/10.1016/j.ccell.2024.05.018/). This highlights the importance of spatial context in determining immune cell behavior and therapeutic responses. Additionally, the studies by Tharp et al. and Perricone et al. emphasized how the fibrotic TME can restrict immune cell infiltration and alter metabolic pathways, suggesting that spatial and temporal factors significantly influence tumor progression and treatment efficacy (ref: Tharp doi.org/10.1038/s43018-024-00775-4/; ref: Perricone doi.org/10.1038/s43018-024-00758-5/). Collectively, these findings underscore the necessity of integrating spatial and temporal analyses into cancer research to develop more effective therapeutic strategies.

Hypoxia is a critical factor influencing tumor progression and therapeutic resistance. Recent studies have focused on the role of hypoxia-inducible factors (HIFs) in mediating cellular responses to low oxygen levels within the tumor microenvironment. Flood et al. discussed the distinct roles of HIF-1α and HIF-2α in transcriptional responses to hypoxia, suggesting that these factors may regulate unique target genes that contribute to tumor growth and survival (ref: Flood doi.org/10.1038/s43018-024-00779-0/). This highlights the potential for targeting HIF pathways as a therapeutic strategy in cancer treatment. Additionally, the work by Tharp et al. and Perricone et al. emphasized how hypoxic conditions in fibrotic tumors can create a metabolic environment that restricts immune cell infiltration and function, particularly CD8+ T cells (ref: Tharp doi.org/10.1038/s43018-024-00775-4/; ref: Perricone doi.org/10.1038/s43018-024-00758-5/). These findings suggest that hypoxia not only promotes tumor progression but also contributes to immune evasion, underscoring the need for therapeutic approaches that can target both hypoxic conditions and the associated metabolic adaptations in tumors. Overall, understanding the interplay between hypoxia and tumor progression is crucial for developing effective cancer therapies.

Innovative therapeutic approaches targeting the tumor microenvironment (TME) are gaining traction as potential strategies to enhance cancer treatment efficacy. Recent studies have explored various modalities, including targeted therapies, immune checkpoint inhibitors, and engineered scaffolds. Zhou et al. developed HRS-4642, a selective KRAS G12D inhibitor, demonstrating significant anti-tumor efficacy in preclinical models, which highlights the potential of targeted therapies in overcoming specific oncogenic mutations (ref: Zhou doi.org/10.1016/j.ccell.2024.06.001/). Additionally, Zhao et al. investigated the combination of fibroblast activation protein (FAP)-targeted radioligand therapy with immune checkpoint blockade, revealing synergistic effects that enhance tumor uptake and retention of therapeutic agents (ref: Zhao doi.org/10.1038/s41392-024-01853-w/). Furthermore, Zhang et al. reported on the use of biodegradable scaffolds to restimulate the antitumor activity of pre-administered CAR-T cells, showing that these scaffolds can create a microenvironment conducive to T cell activation and persistence (ref: Zhang doi.org/10.1038/s41551-024-01216-4/). This approach underscores the importance of engineering the TME to support effective immunotherapy. Moreover, the studies by Tharp et al. and Perricone et al. highlighted the role of TAMs and fibrotic components in the TME, suggesting that targeting these elements could enhance the efficacy of existing therapies (ref: Tharp doi.org/10.1038/s43018-024-00775-4/; ref: Perricone doi.org/10.1038/s43018-024-00758-5/). Overall, these findings illustrate the potential of innovative therapeutic strategies that leverage the TME to improve cancer treatment outcomes.