The immune microenvironment plays a crucial role in tumor progression and response to therapies. A study by Skoulidis et al. highlights that dual immune checkpoint blockade (ICB) with CTLA4 and PD-(L)1 inhibitors significantly enhances anti-tumor activity in advanced non-small-cell lung cancer (NSCLC), although the lack of validated biomarkers for patient selection remains a challenge (ref: Skoulidis doi.org/10.1038/s41586-024-07943-7/). Yang et al. explored the use of non-pathogenic E. coli to deliver IL18 mutein to tumors, demonstrating that this approach can enhance CD8+ T cell responses, thereby overcoming some limitations of the tumor microenvironment (ref: Yang doi.org/10.1038/s41587-024-02418-6/). MacFawn et al. focused on tertiary lymphoid structures (TLSs) in high-grade serous ovarian cancer, revealing that TLS development varies by tumor site and correlates with immune activity, suggesting that spatial characteristics of the immune microenvironment can influence prognosis (ref: MacFawn doi.org/10.1016/j.ccell.2024.09.007/). Furthermore, Fu et al. found that CTLA4 blockade can counteract resistance mechanisms in lung cancer brain metastasis, indicating that the immune microenvironment is a dynamic entity that can be modulated to improve therapeutic outcomes (ref: Fu doi.org/10.1016/j.ccell.2024.09.012/). Overall, these studies underscore the complexity of tumor-immune interactions and the potential for targeted therapies to reshape the immune landscape in favor of anti-tumor responses.

The dynamics of the tumor microenvironment (TME) are critical for understanding cancer progression and treatment response. You et al. investigated the role of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC), revealing that their expression can alter cellular states and the surrounding microenvironment, thus impacting tumor behavior (ref: You doi.org/10.1016/j.cell.2024.09.024/). Fidelle et al. introduced a gene drive system to redirect tumor evolution, suggesting that manipulating the TME can create therapeutic opportunities despite genetic heterogeneity (ref: Fidelle doi.org/10.1038/s41587-024-02429-3/). Liu et al. developed a method for scalable phenotypic screening using pooled perturbations, which could enhance our understanding of TME interactions and cellular responses (ref: Liu doi.org/10.1038/s41587-024-02403-z/). Fitzsimons et al. provided a comprehensive single-cell RNA-seq atlas of intratumoral B cells across various cancers, highlighting the heterogeneity and functional diversity of these immune cells within the TME (ref: Fitzsimons doi.org/10.1016/j.ccell.2024.09.011/). Collectively, these studies illustrate the intricate and evolving nature of the TME and its implications for cancer therapy.

Innovative therapeutic strategies targeting the tumor microenvironment (TME) are emerging as critical components of cancer treatment. Klughammer et al. constructed a multi-modal spatial and cellular map of metastatic breast cancer, revealing how different clinicopathological features influence the TME and potentially therapeutic responses (ref: Klughammer doi.org/10.1038/s41591-024-03215-z/). Alban et al. examined neoantigen immunogenicity in non-small cell lung cancer during nivolumab treatment, finding that early loss of mutations correlates with clinical benefit, emphasizing the need to understand TME interactions for effective immunotherapy (ref: Alban doi.org/10.1038/s41591-024-03240-y/). Zhao et al. highlighted the role of adipocyte-derived glutathione in obesity-related breast cancer, showing that TME metabolites can significantly influence tumor progression (ref: Zhao doi.org/10.1016/j.cmet.2024.09.013/). Deng et al. focused on NFAT5's role in cellular plasticity and resistance to KRAS-targeted therapy in pancreatic cancer, suggesting that TGFβ signaling within the TME is a critical factor in treatment resistance (ref: Deng doi.org/10.1084/jem.20240766/). These findings collectively underscore the importance of targeting the TME to enhance therapeutic efficacy and overcome resistance mechanisms.

Understanding the cellular and molecular mechanisms driving tumor progression is essential for developing effective therapies. Chen et al. investigated the role of proinflammatory immune cells in disrupting angiogenesis in the prenatal brain, revealing insights into how immune interactions can influence vascular development and potentially contribute to tumorigenesis (ref: Chen doi.org/10.1038/s41593-024-01769-2/). Li et al. explored the mechanisms of small cell transformation in EGFR-mutant lung adenocarcinomas, identifying transcriptomic characteristics that may predict transformation and resistance to therapy (ref: Li doi.org/10.1038/s41392-024-01981-3/). The study by Deng et al. on NFAT5 further elucidates how TGFβ signaling promotes epithelial-to-mesenchymal transition (EMT) and resistance to KRAS therapy, highlighting the role of the TME in mediating these processes (ref: Deng doi.org/10.1084/jem.20240766/). Nishimura et al. examined the opposing regulation of the STING pathway in hepatic stellate cells, demonstrating how this regulation can influence hepatocellular carcinoma progression (ref: Nishimura doi.org/10.1016/j.molcel.2024.09.026/). Lastly, Wang et al. identified a splicing isoform of PD-1 that promotes tumor progression, suggesting that alternative splicing may play a role in immune evasion (ref: Wang doi.org/10.1038/s41467-024-53561-2/). Together, these studies provide a comprehensive view of the cellular and molecular underpinnings of tumor progression.

Nanotechnology is revolutionizing cancer therapy by enhancing drug delivery and efficacy. Esplin et al. conducted a multiomic analysis of familial adenomatous polyposis, revealing molecular pathways involved in early tumorigenesis, which can inform the development of targeted nanotherapies (ref: Esplin doi.org/10.1038/s43018-024-00831-z/). Liu et al. described a lysosome-targeting chimeric nanodevice designed for precision tumor therapy, addressing challenges related to bioavailability and specificity in drug delivery (ref: Liu doi.org/10.1021/jacs.4c10010/). The study by Zhao et al. on adipocyte-derived glutathione also underscores the importance of understanding metabolic alterations in the TME, which can be targeted using nanotechnology to improve therapeutic outcomes (ref: Zhao doi.org/10.1016/j.cmet.2024.09.013/). Additionally, the research by Han et al. on NADPH oxidase-inspired biocatalysts highlights the potential of nanotechnology to amplify immune checkpoint blockade therapy through enhanced reactive oxygen species generation (ref: Han doi.org/10.1002/adma.202407644/). These advancements illustrate the transformative potential of nanotechnology in overcoming barriers to effective cancer treatment.

Tumor-associated macrophages (TAMs) play a pivotal role in shaping the tumor microenvironment and influencing immunosuppression. Yang et al. investigated the mechanisms by which lipid metabolism enhances the tumor-promoting effects of TAMs in hepatocellular carcinoma, revealing critical insights into how metabolic alterations can drive tumor progression (ref: Yang doi.org/10.1016/j.jhep.2024.09.029/). Priego et al. focused on the immunosuppressive role of TIMP1 secreted by astrocytes in brain metastasis, demonstrating its impact on CD8+ T cell function and suggesting potential biomarkers for immunotherapy selection (ref: Priego doi.org/10.1158/2159-8290.CD-24-0134/). Nishimura et al. further explored the role of hepatic stellate cells in HCC, showing how p62 regulates the STING pathway and influences the pro-tumorigenic microenvironment (ref: Nishimura doi.org/10.1016/j.molcel.2024.09.026/). Guegan et al. examined the predictive value of the TME on chemotherapy response in undifferentiated pleomorphic sarcomas, highlighting the importance of understanding TAM interactions in treatment outcomes (ref: Guegan doi.org/10.1186/s13045-024-01614-w/). Collectively, these studies emphasize the complex interplay between TAMs and the immune landscape in cancer, underscoring their potential as therapeutic targets.

Spatial and single-cell analysis techniques are advancing our understanding of the tumor microenvironment (TME) at unprecedented resolution. Migliorini et al. investigated the role of embryonic macrophages in pancreatic differentiation, highlighting the importance of immune cell interactions in shaping the TME during organogenesis (ref: Migliorini doi.org/10.1016/j.stem.2024.09.011/). Hu et al. developed a near-infrared actuated nanomotor for enhanced tumor penetration and therapy, showcasing how innovative technologies can improve therapeutic delivery within the TME (ref: Hu doi.org/10.1002/adma.202412227/). Jeon et al. explored the immunomodulatory function of contactin-4, revealing its role in suppressing T cell responses within the tumor context (ref: Jeon doi.org/10.1126/sciimmunol.adk7237/). Han et al. designed NADPH oxidase-inspired biocatalysts to amplify immune checkpoint blockade therapy, demonstrating the potential of spatially targeted therapies to overcome immunosuppression in the TME (ref: Han doi.org/10.1002/adma.202407644/). Fan et al. identified the co-location of MARCO+ TAMs and CTSE+ tumor cells as a poor prognostic indicator in intrahepatic cholangiocarcinoma, emphasizing the significance of spatial relationships in tumor biology (ref: Fan doi.org/10.1097/HEP.0000000000001138/). These studies collectively highlight the transformative impact of spatial and single-cell analyses in elucidating the complexities of the TME.

Metabolic alterations within the tumor microenvironment (TME) significantly influence cancer progression and treatment responses. Zhao et al. demonstrated that adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex, indicating how metabolic changes in the TME can drive tumor growth (ref: Zhao doi.org/10.1016/j.cmet.2024.09.013/). Guegan et al. examined the predictive value of the TME on pathologic response to neoadjuvant chemotherapy in undifferentiated pleomorphic sarcomas, highlighting the variability in metabolic responses among patients (ref: Guegan doi.org/10.1186/s13045-024-01614-w/). Li et al. developed high-performance fluorescent biosensors to track arginine metabolism, revealing its functional diversity in physiological and pathological contexts, which may have implications for therapeutic targeting (ref: Li doi.org/10.1016/j.cmet.2024.09.011/). Nishimura et al. explored the role of p62 in regulating the STING pathway in hepatic stellate cells, linking metabolic alterations to immune responses in hepatocellular carcinoma (ref: Nishimura doi.org/10.1016/j.molcel.2024.09.026/). These findings underscore the critical role of metabolic dynamics in shaping the TME and influencing cancer therapy outcomes.