The tumor microenvironment (TME) plays a crucial role in cancer progression and therapy response. Recent studies have highlighted the complexity of the TME, particularly in high-grade serous ovarian cancer (HGSOC), where single-cell gene expression and T cell receptor profiling revealed significant insights into the immune landscape and therapeutic targeting of effector Treg cells in homologous-recombination-deficient tumors (ref: Luo doi.org/10.1016/j.cell.2024.06.013/). Additionally, patient-derived mini-colons have been developed to model TME complexity, addressing limitations of traditional organoid models by incorporating multicellular diversity and tissue-level organization (ref: Lorenzo-Martín doi.org/10.1038/s41587-024-02301-4/). Extracellular vesicles (EVs) have emerged as valuable biomarkers for monitoring metastatic prostate cancer, with genomic and transcriptomic profiling of EV-DNA and EV-RNA demonstrating their potential to reflect tumor characteristics and treatment responses (ref: Casanova-Salas doi.org/10.1016/j.ccell.2024.06.003/). Furthermore, spatiotemporal single-cell analysis in colorectal cancer has elucidated cellular dynamics that correlate with immunotherapy responses, revealing distinct immune programs associated with treatment outcomes (ref: Chen doi.org/10.1016/j.ccell.2024.06.009/). The interplay between Tregs and dendritic cells in lymphatic regions has been shown to limit antigen trafficking, thereby restraining anti-tumor immunity (ref: You doi.org/10.1016/j.ccell.2024.06.014/). In melanoma, adoptive cell therapy with tumor-infiltrating lymphocytes has demonstrated efficacy, particularly when considering prior anti-PD-(L)1 therapy (ref: Martín-Lluesma doi.org/10.1016/j.annonc.2024.07.723/). Lastly, innovative therapeutic approaches, such as a bispecific nanosystem targeting bone marrow, have been developed to enhance natural killer cell activation against hematologic malignancies (ref: Zhang doi.org/10.1038/s41565-024-01736-9/).

The immune response in cancer therapy is increasingly understood through the lens of cellular dynamics and the tumor microenvironment. A pivotal study on colorectal cancer utilized spatiotemporal single-cell analysis to map immune responses to PD-1 blockade, revealing distinct cellular programs that correlate with treatment efficacy (ref: Chen doi.org/10.1016/j.ccell.2024.06.009/). Additionally, the interaction between regulatory T cells (Tregs) and myeloid cells has been shown to limit antigen trafficking and hinder anti-tumor immunity, emphasizing the need for strategies that disrupt these interactions (ref: You doi.org/10.1016/j.ccell.2024.06.014/). In a phase 2 trial, personalized neoantigen-reactive TCR-transduced T cells demonstrated promising results in metastatic colorectal cancer, highlighting the potential of adoptive cell transfer therapies (ref: Parkhurst doi.org/10.1038/s41591-024-03109-0/). Furthermore, a randomized phase 3 trial investigated the combination of a novel PD-L1 inhibitor with chemotherapy in extensive-stage small-cell lung cancer, suggesting that immunochemotherapy may enhance treatment outcomes (ref: Cheng doi.org/10.1038/s41591-024-03132-1/). The role of the gut microbiome in modulating immune responses was also underscored by a clinical trial combining fecal microbiota transplantation with anti-PD-1 therapy, which resulted in improved efficacy in patients refractory to standard treatment (ref: Kim doi.org/10.1016/j.chom.2024.06.010/). Lastly, the presence of intratumoral Escherichia was associated with improved survival outcomes in patients receiving immune checkpoint inhibitors for advanced non-small-cell lung cancer, suggesting a potential microbiome influence on treatment efficacy (ref: Elkrief doi.org/10.1200/JCO.23.01488/).

The extracellular matrix (ECM) is increasingly recognized for its role in cancer progression and therapy resistance. A study on pancreatic ductal adenocarcinoma (PDAC) utilized engineered matrices to demonstrate that stiffness-mediated chemoresistance is a significant factor in tumor behavior, highlighting the need to consider ECM properties in therapeutic strategies (ref: LeSavage doi.org/10.1038/s41563-024-01908-x/). Additionally, research into hypoxia-induced mechanisms revealed that UQCC3, a mitochondrial protein, translocates to the nucleus in hepatocellular carcinoma, suggesting a novel pathway through which the ECM influences tumor adaptation to hypoxic conditions (ref: Yang doi.org/10.1038/s41392-024-01909-x/). Radiotherapy has also been shown to trigger the reduction of platinum-based chemotherapeutic prodrugs in tumors, enhancing their cytotoxic effects, which could inform future combination therapies (ref: Fu doi.org/10.1038/s41551-024-01239-x/). The development of site-specific antibody prodrugs aims to improve therapeutic specificity and reduce off-target effects, representing a promising advancement in antibody-based therapies (ref: Tao doi.org/10.1021/jacs.4c04035/). Furthermore, the characterization of cancer-associated endocrine cells in PDAC has revealed their potential role in tumorigenesis, expanding the understanding of the TME's cellular composition (ref: Chen doi.org/10.1053/j.gastro.2024.07.016/). Lastly, the NeoPembrOv trial's immunomic profiling identified key drivers of immunoresistance in high-grade ovarian carcinoma, underscoring the importance of the ECM in shaping immune responses (ref: Le Saux doi.org/10.1038/s41467-024-47000-5/).

Cancer stem cells (CSCs) are pivotal in understanding tumor resistance mechanisms and therapeutic failures. A study identified chemotherapy-resistant persister cells in high-risk neuroblastoma, utilizing single-nucleus RNA sequencing to uncover the cellular characteristics that contribute to relapse (ref: Grossmann doi.org/10.1158/2159-8290.CD-24-0046/). Additionally, the release of interleukin-33 by CSCs within large oncosomes has been shown to promote an immunosuppressive environment by differentiating macrophage precursors, thereby facilitating tumor progression (ref: Erickson doi.org/10.1016/j.immuni.2024.07.004/). The gut microbiome's influence on immune checkpoint inhibitor efficacy was highlighted in a clinical trial where fecal microbiota transplantation improved outcomes in patients with anti-PD-1-refractory cancers, suggesting that microbiome modulation could enhance therapeutic responses (ref: Kim doi.org/10.1016/j.chom.2024.06.010/). Furthermore, targeting the glucocorticoid receptor-CCR8 axis has been proposed as a strategy to enhance T cell infiltration in brain tumors, addressing the systemic immunosuppression that limits the effectiveness of immunotherapies in these malignancies (ref: Zhang doi.org/10.1038/s41423-024-01202-5/). In multiple myeloma, genomic and immune determinants of resistance to daratumumab-based therapy were explored, revealing insights into the mechanisms underlying treatment failure (ref: Ziccheddu doi.org/10.1038/s41408-024-01096-6/). Lastly, the neurotransmitter calcitonin gene-related peptide was found to shape an immunosuppressive microenvironment in medullary thyroid cancer, indicating the multifaceted roles of neuro-immune interactions in tumor biology (ref: Hou doi.org/10.1038/s41467-024-49824-7/).

Metabolic reprogramming is a critical aspect of tumor biology that influences cancer progression and treatment responses. A study on the adoptive transfer of personalized neoantigen-reactive TCR-transduced T cells in metastatic colorectal cancer demonstrated that metabolic adaptations in T cells can mediate cancer regression, highlighting the importance of tailoring immunotherapies to the metabolic state of both the tumor and the immune cells (ref: Parkhurst doi.org/10.1038/s41591-024-03109-0/). Additionally, research on the radiation-induced reduction of platinum-based chemotherapeutic prodrugs revealed a novel mechanism by which radiotherapy can enhance the efficacy of chemotherapy, suggesting that metabolic pathways may be targeted to improve treatment outcomes (ref: Fu doi.org/10.1038/s41551-024-01239-x/). Furthermore, targeting the glucocorticoid receptor-CCR8 axis in intracranial cancers has been shown to enhance T cell infiltration, addressing the metabolic and immunosuppressive barriers that limit therapeutic efficacy in brain tumors (ref: Zhang doi.org/10.1038/s41423-024-01202-5/). These findings underscore the intricate relationship between metabolism and immune responses in the tumor microenvironment, paving the way for innovative therapeutic strategies that leverage metabolic vulnerabilities.

Tumor-associated macrophages (TAMs) and myeloid cells are integral to the tumor microenvironment, influencing immune responses and treatment outcomes. A pan-cancer atlas study has advanced the characterization of macrophage phenotypes beyond the traditional M1/M2 classification, revealing a diverse spectrum of macrophage subsets that regulate immunotherapy responses (ref: Coulton doi.org/10.1038/s41467-024-49885-8/). This comprehensive approach provides a valuable resource for understanding the role of TAMs in various cancers. In multiple myeloma, the genomic and immune determinants of resistance to daratumumab-based therapy were investigated, highlighting the complex interplay between myeloid cells and tumor cells in mediating treatment resistance (ref: Ziccheddu doi.org/10.1038/s41408-024-01096-6/). Additionally, the neurotransmitter calcitonin gene-related peptide was found to contribute to an immunosuppressive microenvironment in medullary thyroid cancer, emphasizing the role of neuro-immune interactions in shaping tumor progression (ref: Hou doi.org/10.1038/s41467-024-49824-7/). These studies collectively underscore the importance of targeting myeloid cell dynamics and their interactions with tumor cells to enhance therapeutic efficacy and overcome resistance mechanisms.

Recent advancements in genomic and transcriptomic analyses have provided deeper insights into cancer biology and treatment responses. Whole genome sequencing of clear cell renal cell carcinoma (ccRCC) patients has refined the understanding of its genomic landscape, identifying candidate driver genes and emphasizing the role of epigenetic regulation in tumor progression (ref: Culliford doi.org/10.1038/s41467-024-49692-1/). Similarly, single-cell multiomics studies have revealed how mutations in epigenetic regulators, such as ENL, disrupt kidney development and contribute to tumorigenesis in Wilms tumor (ref: Song doi.org/10.1038/s41467-024-50171-w/). Furthermore, a comprehensive analysis of primary and metastatic renal cell carcinoma tumors has characterized genomic and transcriptomic features, shedding light on the molecular mechanisms driving metastatic spread (ref: Gulati doi.org/10.1172/JCI176230/). The development of SANTO, a method for aligning and stitching spatial omics data, represents a significant technological advancement that will facilitate a holistic understanding of tumor microenvironments (ref: Li doi.org/10.1038/s41467-024-50308-x/). Lastly, the investigation of necroptosis in pancreatic cancer has uncovered its role in enhancing the 'don't eat me' signal, thereby promoting liver metastasis, which underscores the importance of understanding cell death mechanisms in cancer progression (ref: Liao doi.org/10.1038/s41467-024-50450-6/).