Recent studies have significantly advanced our understanding of the tumor immune microenvironment and its implications for cancer therapy. Dolton et al. explored the antigen specificity of T cell receptors (TCRs) following tumor-infiltrating lymphocyte (TIL) therapy in stage IV malignant melanoma, revealing that individual TCRs can target multiple tumor types via HLA A, suggesting a broader applicability of TIL therapy across different cancers (ref: Dolton doi.org/10.1016/j.cell.2023.06.020/). In a complementary approach, Zhang et al. integrated lipid nanoparticle-mRNA formulations with dendritic cell therapy to overcome immunosuppressive factors in the tumor microenvironment, demonstrating that this combination can induce robust immunogenic cell death and enhance T cell activation (ref: Zhang doi.org/10.1038/s41565-023-01453-9/). Sattiraju et al. highlighted the role of hypoxic niches in glioblastoma, showing that these areas attract and sequester tumor-associated macrophages and cytotoxic T cells, ultimately reprogramming them for immunosuppression, which complicates therapeutic efficacy (ref: Sattiraju doi.org/10.1016/j.immuni.2023.06.017/). Furthermore, Tang et al. examined the immunometabolic coevolution in clear cell renal cell carcinoma (ccRCC), revealing that intratumoral metabolite heterogeneity shapes both tumor cell phenotypes and immune responses, indicating a complex interplay between metabolism and immunity (ref: Tang doi.org/10.1016/j.cmet.2023.06.005/). Wang et al. introduced an antibody-guided IL-2 pro-cytokine that rejuvenates dysfunctional CD8 T cells, demonstrating its potential to enhance anti-tumor immunity in a bilateral tumor model (ref: Wang doi.org/10.1038/s41392-023-01463-y/). Collectively, these studies underscore the multifaceted nature of the tumor immune microenvironment and the need for innovative strategies to enhance immunotherapy outcomes.

The dynamics of the tumor microenvironment (TME) play a crucial role in cancer progression and treatment response. Jeon et al. investigated the effects of radiation therapy on glioblastoma, identifying tissue factor (CD142) as a critical regulator that promotes radio-resistance and tumor recurrence through its induction in senescent tumor cells (ref: Jeon doi.org/10.1016/j.ccell.2023.06.007/). This finding highlights the need to understand TME alterations post-therapy to improve treatment strategies. In pancreatic cancer, Huang et al. demonstrated that BICC1 drives VEGF-independent angiogenesis, correlating with increased microvessel density and tumor growth, suggesting that targeting this pathway could enhance therapeutic efficacy (ref: Huang doi.org/10.1038/s41392-023-01478-5/). Gutierrez et al. reported on the phase 2 KEYNOTE-495 trial, which emphasizes the importance of biomarker-directed therapies in non-small cell lung cancer (NSCLC), revealing that only a subset of patients responds to pembrolizumab due to the heterogeneity of the TME (ref: Gutierrez doi.org/10.1038/s41591-023-02385-6/). Additionally, Andriantsitohaina et al. explored the role of extracellular vesicles in liver metastasis from colorectal cancer, uncovering their prometastatic and immunosuppressive properties, which could inform future therapeutic approaches (ref: Andriantsitohaina doi.org/10.1016/j.tcb.2023.07.001/). These studies collectively illustrate the dynamic and complex interactions within the TME that influence tumor behavior and treatment responses.

The interplay between cancer metabolism and therapy resistance is increasingly recognized as a critical factor in tumor progression. Sattiraju et al. documented how hypoxic niches in glioblastoma attract tumor-associated macrophages and cytotoxic T cells, leading to their reprogramming for immunosuppression, which complicates therapeutic efficacy (ref: Sattiraju doi.org/10.1016/j.immuni.2023.06.017/). This finding underscores the importance of targeting metabolic pathways to enhance immune responses. Wang et al. introduced an antibody-guided IL-2 pro-cytokine that rejuvenates dysfunctional CD8 T cells, demonstrating its potential to enhance anti-tumor immunity in a bilateral tumor model (ref: Wang doi.org/10.1038/s41392-023-01463-y/). Hu et al. focused on HER2-positive gastric cancer, revealing that glutamine metabolism drives M2 macrophage polarization, which mediates resistance to trastuzumab. Their findings suggest that combining therapies targeting glutamine metabolism and promoting M1 polarization could effectively reverse resistance (ref: Hu doi.org/10.1002/cac2.12459/). Zhang et al. explored the role of prolonged hypoxia in promoting necroptosis through RIPK1 activation, highlighting a potential mechanism by which hypoxic conditions can lead to inflammation and cell death, independent of traditional pathways (ref: Zhang doi.org/10.1038/s41556-023-01170-4/). These studies illustrate the critical role of metabolic adaptations in shaping tumor behavior and resistance to therapies.

The integration of biomarkers into cancer therapy is pivotal for personalizing treatment approaches. Gutierrez et al. reported interim results from the phase 2 KEYNOTE-495 trial, which investigates biomarker-directed pembrolizumab-based combination therapies in advanced non-small cell lung cancer (NSCLC). Their findings indicate that only a subset of patients benefits from pembrolizumab due to the heterogeneity of the tumor microenvironment, emphasizing the need for tailored therapeutic strategies (ref: Gutierrez doi.org/10.1038/s41591-023-02385-6/). Farin et al. established a colorectal cancer organoid-stroma biobank to assess individualized therapy responses, allowing for subtype-specific evaluations that reflect the cellular heterogeneity of tumors (ref: Farin doi.org/10.1158/2159-8290.CD-23-0050/). In breast cancer, Schuster et al. conducted a molecular profiling study to identify features associated with resistance to aromatase inhibitors, revealing critical insights into the mechanisms underlying treatment failure (ref: Schuster doi.org/10.1038/s41467-023-39613-z/). These studies collectively highlight the importance of biomarker-driven approaches in enhancing the efficacy of cancer therapies and addressing treatment resistance.

Tumor-associated fibroblasts (TAFs) and the extracellular matrix (ECM) play significant roles in shaping the tumor microenvironment and influencing cancer progression. Wang et al. demonstrated that targeting the tumor microenvironment with an antibody-guided IL-2 pro-cytokine can rejuvenate dysfunctional CD8 T cells, suggesting that manipulating TAFs and ECM components may enhance anti-tumor immunity (ref: Wang doi.org/10.1038/s41392-023-01463-y/). Additionally, Wang et al. explored the concept of pathogen-tumor symbionts, highlighting how intratumoral bacteria can contribute to cancer progression and metastasis, indicating that targeting these interactions could provide new therapeutic avenues (ref: Wang doi.org/10.1038/s41392-023-01491-8/). Furthermore, the study by Wang et al. on oncolytic viruses showed that engineering these viruses to enforce cholesterol efflux can restore phagocytic function in tumor-associated macrophages, thereby enhancing anti-tumor immunity in glioblastoma (ref: Wang doi.org/10.1038/s41467-023-39683-z/). These findings underscore the complex interplay between TAFs, the ECM, and immune cells in the tumor microenvironment, suggesting that targeting these components may improve therapeutic outcomes.

Angiogenesis and vascular dynamics are critical factors in tumor growth and metastasis. Huang et al. identified BICC1 as a key driver of VEGF-independent angiogenesis in pancreatic cancer, correlating its overexpression with increased microvessel density and poor prognosis. Their findings suggest that targeting BICC1 could enhance the efficacy of existing therapies by reducing tumor vascularization (ref: Huang doi.org/10.1038/s41392-023-01478-5/). Jeon et al. examined the effects of radiation therapy on glioblastoma, revealing that tissue factor (CD142) is induced in senescent tumor cells post-irradiation, promoting clonal expansion and potentially contributing to radio-resistance (ref: Jeon doi.org/10.1016/j.ccell.2023.06.007/). This highlights the need for strategies that address vascular changes induced by therapy. Gutierrez et al. reported on the phase 2 KEYNOTE-495 trial, emphasizing the importance of biomarker-directed therapies in NSCLC, where vascular dynamics may influence treatment responses (ref: Gutierrez doi.org/10.1038/s41591-023-02385-6/). Collectively, these studies illustrate the intricate relationship between angiogenesis, vascular dynamics, and therapeutic outcomes in cancer.

Hypoxia is a critical factor influencing tumor progression and therapeutic resistance. Sattiraju et al. documented how hypoxic niches in glioblastoma attract and sequester tumor-associated macrophages and cytotoxic T cells, leading to their reprogramming for immunosuppression, which complicates therapeutic efficacy (ref: Sattiraju doi.org/10.1016/j.immuni.2023.06.017/). Zhang et al. explored the role of prolonged hypoxia in promoting necroptosis through RIPK1 activation, highlighting a potential mechanism by which hypoxic conditions can lead to inflammation and cell death, independent of traditional pathways (ref: Zhang doi.org/10.1038/s41556-023-01170-4/). Tang et al. examined the immunometabolic coevolution in clear cell renal cell carcinoma (ccRCC), revealing that intratumoral metabolite heterogeneity shapes both tumor cell phenotypes and immune responses, indicating a complex interplay between metabolism and hypoxia (ref: Tang doi.org/10.1016/j.cmet.2023.06.005/). These studies collectively underscore the importance of targeting hypoxic conditions to enhance therapeutic responses and improve patient outcomes.

Cellular signaling pathways play a pivotal role in tumorigenesis and therapeutic responses. Andriantsitohaina et al. investigated the role of extracellular vesicles in liver metastasis from colorectal cancer, uncovering their prometastatic and immunosuppressive properties, which could inform future therapeutic approaches (ref: Andriantsitohaina doi.org/10.1016/j.tcb.2023.07.001/). Wang et al. demonstrated that targeting the tumor microenvironment with an antibody-guided IL-2 pro-cytokine can rejuvenate dysfunctional CD8 T cells, suggesting that manipulating signaling pathways within the TME may enhance anti-tumor immunity (ref: Wang doi.org/10.1038/s41392-023-01463-y/). Chen et al. developed a nanosystem that integrates nanosonosensitizers with tumor metabolism regulation effects for synergistic sonodynamic-immunometabolic therapy, highlighting the importance of metabolic signaling in cancer treatment (ref: Chen doi.org/10.1002/adma.202304246/). These studies illustrate the critical role of cellular signaling in shaping tumor behavior and responses to therapy.