The tumor microenvironment (TME) plays a critical role in cancer progression and therapeutic response, particularly in glioblastoma and colorectal cancer. Kloosterman et al. demonstrated that macrophages facilitate the transfer of myelin-derived lipids to glioblastoma cells, supporting their metabolic demands through an LXR/Abca1-dependent mechanism, thus highlighting a unique immune-metabolic interplay in the TME (ref: Kloosterman doi.org/10.1016/j.cell.2024.07.030/). In advanced melanoma, Cillo et al. found that the combination of anti-LAG-3 and anti-PD-1 therapies enhances CD8+ T cell functionality, suggesting that immune checkpoint blockade can reshape T cell responses in the TME (ref: Cillo doi.org/10.1016/j.cell.2024.06.036/). Tan et al. introduced metal-ion-chelating L-phenylalanine nanostructures that, when combined with short-term starvation, remodel the immunosuppressive microenvironment of breast tumors, enhancing the efficacy of immune checkpoint inhibitors (ref: Tan doi.org/10.1038/s41565-024-01758-3/). Furthermore, Jackson et al. identified Meteorin-like cytokine as a contributor to CD8+ T cell hypofunction in the TME, linking metabolic insufficiency to immune evasion (ref: Jackson doi.org/10.1016/j.immuni.2024.07.003/). Integrative single-cell analysis by Chu et al. revealed distinct immune evasion mechanisms in colorectal cancer, emphasizing the heterogeneity of the TME and its impact on patient stratification (ref: Chu doi.org/10.1038/s43018-024-00807-z/). Soll et al. highlighted the role of sodium chloride in enhancing T cell metabolic fitness and cytotoxicity, suggesting ionic signals as potential modulators of antitumor immunity (ref: Soll doi.org/10.1038/s41590-024-01918-6/). In HER2-positive gastric cancer, Chen et al. found that PD-L1 expression correlates with immune microenvironment variations, influencing treatment outcomes (ref: Chen doi.org/10.1186/s12943-024-02085-w/). Zhou et al. proposed targeting circ-0034880-enriched tumor extracellular vesicles to impede pre-metastatic niche formation, indicating a novel therapeutic strategy against metastasis (ref: Zhou doi.org/10.1186/s12943-024-02086-9/). Lastly, Qiu et al. demonstrated that breast cancer cells adapt to glutamine blockade through metabolic reprogramming, underscoring the importance of metabolic pathways in the TME (ref: Qiu doi.org/10.1038/s42255-024-01104-w/).

Metabolic adaptations are crucial for cancer cells to thrive in hostile environments, as evidenced by several studies. Jia et al. linked high expression of oleoyl-ACP hydrolase to severe respiratory viral diseases, suggesting that metabolic pathways may also influence cancer susceptibility (ref: Jia doi.org/10.1016/j.cell.2024.07.026/). Argentieri et al. developed a proteomic aging clock that predicts mortality and age-related diseases, indicating that metabolic profiling could be a valuable tool in cancer prognosis (ref: Argentieri doi.org/10.1038/s41591-024-03164-7/). Yeh et al. explored the spatial organization of ovarian cancer, identifying genetic regulators that influence immune evasion and metabolic states, which could inform therapeutic strategies (ref: Yeh doi.org/10.1038/s41590-024-01943-5/). Qiu et al. further demonstrated that breast cancer cells adapt to glutamine starvation through AMPK-mediated upregulation of the serine synthesis pathway, revealing a metabolic flexibility that may contribute to treatment resistance (ref: Qiu doi.org/10.1038/s42255-024-01104-w/). Kobayashi et al. highlighted the neuro-mesenchymal interactions that promote colorectal cancer progression, suggesting that metabolic crosstalk between cancer-associated fibroblasts and nerves could be targeted therapeutically (ref: Kobayashi doi.org/10.1158/2159-8290.CD-24-0287/). Sun et al. showed that loss of 53BP1 activates the cGAS-STING pathway, linking DNA damage response to metabolic adaptations and antitumor immunity (ref: Sun doi.org/10.1038/s41467-024-50999-2/). Lastly, Graham et al. provided insights into MYC-driven prostate cancer, revealing convergent alterations in the TME that may influence metabolic pathways and tumor progression (ref: Graham doi.org/10.1038/s41467-024-51450-2/).

Innovative therapeutic strategies targeting the tumor microenvironment (TME) are emerging as promising approaches in cancer treatment. Choueiri et al. conducted a phase 3 trial comparing belzutifan and everolimus in advanced renal-cell carcinoma, demonstrating that belzutifan significantly improved progression-free survival, particularly in patients previously treated with immune checkpoint inhibitors (ref: Choueiri doi.org/10.1056/NEJMoa2313906/). Nguyen et al. developed charge-convertible cyclodextrin nanoparticles that enhance tumor penetration and imaging capabilities, showcasing the potential of nanotechnology in improving therapeutic delivery (ref: Nguyen doi.org/10.1038/s41565-024-01757-4/). Dai et al. introduced a hybrid system that augments antitumor immunity through genetic engineering of both bacteria and tumor cells, providing a novel strategy for enhancing immunotherapy efficacy (ref: Dai doi.org/10.1002/adma.202407927/). Roetzer-Pejrimovsky et al. utilized deep learning to link digital pathology phenotypes with patient outcomes in glioblastoma, emphasizing the role of advanced imaging techniques in personalized therapy (ref: Roetzer-Pejrimovsky doi.org/10.1093/gigascience/). Han et al. demonstrated that probiotics functionalized with a gallium-polyphenol network can modulate the intratumor microbiota, promoting anti-tumor immune responses in pancreatic cancer (ref: Han doi.org/10.1038/s41467-024-51534-z/). White et al. assessed various deconvolution methods for inferring immune cell composition from bulk gene expression, highlighting the importance of accurate immune profiling in understanding TME dynamics (ref: White doi.org/10.1038/s41467-024-50618-0/). These studies collectively underscore the significance of targeting the TME to enhance therapeutic outcomes in cancer treatment.

The interactions between the extracellular matrix (ECM) and stromal cells are pivotal in shaping the tumor microenvironment and influencing cancer progression. Kousa et al. investigated age-related changes in thymic epithelial cells, revealing how alterations in stromal cells can limit thymic function and regeneration, which may have implications for immune responses in cancer (ref: Kousa doi.org/10.1038/s41590-024-01915-9/). Kobayashi et al. highlighted the role of cancer-associated fibroblasts and nerves in promoting colorectal cancer progression through neuro-mesenchymal interactions, suggesting that targeting these pathways could provide therapeutic benefits (ref: Kobayashi doi.org/10.1158/2159-8290.CD-24-0287/). Yeh et al. mapped spatial organization and genetic regulators in ovarian cancer, identifying how stromal interactions can drive immune evasion and affect treatment responses (ref: Yeh doi.org/10.1038/s41590-024-01943-5/). Das et al. conducted multi-omics analyses of hepatocellular carcinoma in Hispanic patients, revealing molecular alterations that may be influenced by the ECM and stromal components (ref: Das doi.org/10.1093/jnci/). Shan et al. proposed a novel strategy for treating metabolic dysfunction-associated steatohepatitis by enhancing mRNA delivery in fibrotic regions, demonstrating the potential of ECM-targeted therapies (ref: Shan doi.org/10.1038/s41467-024-51571-8/). These findings emphasize the importance of understanding ECM and stromal interactions in developing effective cancer therapies.

Tumor angiogenesis and vascularization are critical processes that influence tumor growth and response to therapy. Choueiri et al. demonstrated that belzutifan significantly improves progression-free survival in advanced renal-cell carcinoma, highlighting the importance of targeting angiogenesis in treatment strategies (ref: Choueiri doi.org/10.1056/NEJMoa2313906/). Lu et al. explored the normalization of tumor vasculature using modified C-type natriuretic peptide, which reinvigorates antitumor immunity and enhances the efficacy of solid tumor therapies, suggesting that vascular normalization can improve therapeutic outcomes (ref: Lu doi.org/10.1126/scitranslmed.adn0904/). Dai et al. introduced a hybrid system that enhances antitumor immunity through simultaneous regulation of immune and tumor cells, indicating that effective vascularization strategies can augment immunotherapy (ref: Dai doi.org/10.1002/adma.202407927/). Han et al. showed that probiotics functionalized with a gallium-polyphenol network can modulate the intratumor microbiota and promote anti-tumor immune responses, further emphasizing the interplay between vascularization and immune modulation in cancer (ref: Han doi.org/10.1038/s41467-024-51534-z/). These studies collectively underscore the significance of targeting tumor angiogenesis and vascularization to enhance therapeutic efficacy in cancer treatment.

Hypoxia is a critical factor influencing tumor progression and therapeutic resistance. Sun et al. demonstrated that loss of 53BP1 leads to activation of the cGAS-STING pathway, linking DNA damage response to hypoxic conditions and antitumor immunity in ovarian and pancreatic cancer (ref: Sun doi.org/10.1038/s41467-024-50999-2/). Qiu et al. highlighted how breast cancer cells adapt to glutamine blockade through metabolic reprogramming, suggesting that hypoxic conditions may drive metabolic adaptations that contribute to treatment resistance (ref: Qiu doi.org/10.1038/s42255-024-01104-w/). Graham et al. provided insights into MYC-driven prostate cancer, revealing convergent alterations in the TME that may be influenced by hypoxic conditions, thereby affecting tumor progression (ref: Graham doi.org/10.1038/s41467-024-51450-2/). Das et al. conducted multi-omics analyses of hepatocellular carcinoma in Hispanic patients, elucidating molecular alterations that may be exacerbated by hypoxic environments (ref: Das doi.org/10.1093/jnci/). These findings collectively emphasize the role of hypoxia in shaping tumor biology and therapeutic responses.

Understanding the cellular and molecular mechanisms of tumorigenesis is essential for developing effective cancer therapies. Jia et al. linked high expression of oleoyl-ACP hydrolase to severe respiratory viral diseases, suggesting that metabolic pathways may also play a role in cancer susceptibility (ref: Jia doi.org/10.1016/j.cell.2024.07.026/). Kobayashi et al. explored neuro-mesenchymal interactions in colorectal cancer, revealing how these interactions can promote tumor progression and suggesting potential therapeutic strategies (ref: Kobayashi doi.org/10.1158/2159-8290.CD-24-0287/). Sun et al. demonstrated that loss of 53BP1 activates the cGAS-STING pathway, linking DNA damage response to tumorigenesis and immune activation (ref: Sun doi.org/10.1038/s41467-024-50999-2/). Graham et al. provided insights into MYC-driven prostate cancer, revealing convergent alterations in the TME that may influence tumorigenesis (ref: Graham doi.org/10.1038/s41467-024-51450-2/). These studies collectively highlight the importance of understanding the underlying mechanisms of tumorigenesis to inform therapeutic approaches.

Innovative nanotechnology approaches are transforming cancer therapy by enhancing drug delivery and therapeutic efficacy. Nguyen et al. developed charge-convertible cyclodextrin nanoparticles that achieve deep tumor penetration, demonstrating their potential as theranostic agents for rectal cancer (ref: Nguyen doi.org/10.1038/s41565-024-01757-4/). Dai et al. introduced a hybrid system that enhances antitumor immunity through genetic engineering of both bacteria and tumor cells, showcasing the potential of combining nanotechnology with immunotherapy (ref: Dai doi.org/10.1002/adma.202407927/). Han et al. demonstrated that probiotics functionalized with a gallium-polyphenol network can modulate the intratumor microbiota, promoting anti-tumor immune responses in pancreatic cancer (ref: Han doi.org/10.1038/s41467-024-51534-z/). White et al. assessed various deconvolution methods for inferring immune cell composition from bulk gene expression, emphasizing the importance of accurate immune profiling in the context of nanotechnology applications (ref: White doi.org/10.1038/s41467-024-50618-0/). These studies collectively highlight the transformative potential of nanotechnology in enhancing cancer therapy and improving patient outcomes.