The tumor microenvironment (TME) plays a critical role in cancer progression and treatment resistance. Recent studies have highlighted the complexity of the TME, particularly in glioblastoma, where intratumoral heterogeneity and tumor evolution contribute to treatment failure. Mathur et al. utilized 3D neuronavigation during surgical resection to acquire samples from glioblastoma, revealing genomic, epigenomic, and microenvironmental heterogeneity through integrative tissue and single-cell analysis (ref: Mathur doi.org/10.1016/j.cell.2023.12.013/). Similarly, Pozniak et al. explored the melanoma ecosystem and identified a TCF4-dependent gene regulatory network that promotes resistance to immunotherapy, emphasizing the role of the TME in shaping tumor cell states (ref: Pozniak doi.org/10.1016/j.cell.2023.11.037/). In small cell lung cancer, Liu et al. performed a comprehensive proteogenomic characterization, identifying subtype-specific therapeutic strategies and prognostic biomarkers, further illustrating the TME's influence on cancer biology (ref: Liu doi.org/10.1016/j.cell.2023.12.004/). The interplay between tumor cells and their microenvironment is also evident in studies on brain metastasis, where Bejarano et al. interrogated endothelial and mural cells to uncover immune-regulatory mechanisms critical for metastatic progression (ref: Bejarano doi.org/10.1016/j.ccell.2023.12.018/). Overall, these studies underscore the necessity of understanding TME dynamics for developing effective therapeutic strategies.

Immunotherapy has revolutionized cancer treatment, yet resistance remains a significant challenge. Recent research has focused on understanding the mechanisms underlying resistance to immune checkpoint blockade (ICB). Memon et al. investigated acquired resistance in non-small cell lung cancer (NSCLC) and found that persistent IFN signaling and mutations in antigen presentation genes are associated with resistance, highlighting the complexity of immune responses in the TME (ref: Memon doi.org/10.1016/j.ccell.2023.12.013/). In triple-negative breast cancer, Shiao et al. employed single-cell transcriptomics and spatial proteomics to identify response trajectories to pembrolizumab and radiation therapy, revealing that non-responders exhibit minimal immune changes, suggesting a need for combination therapies to enhance efficacy (ref: Shiao doi.org/10.1016/j.ccell.2023.12.012/). Additionally, Goddard et al. explored immune evasion by dormant disseminated tumor cells (DTCs), demonstrating that T cell immunotherapies can overcome this evasion despite DTCs downregulating major histocompatibility complex I (ref: Goddard doi.org/10.1016/j.ccell.2023.12.011/). These findings collectively emphasize the importance of understanding resistance mechanisms to optimize immunotherapy outcomes.

Single-cell and spatial profiling techniques have emerged as powerful tools for dissecting tumor heterogeneity and the TME. Shiao et al. utilized these methods to analyze triple-negative breast cancer biopsies, identifying distinct response trajectories to immunotherapy and radiation, which could inform personalized treatment strategies (ref: Shiao doi.org/10.1016/j.ccell.2023.12.012/). Hoekstra et al. focused on the spatiotemporal dynamics of CD8+ T cells within the TME, revealing insights into how cytokine signaling influences anti-tumor responses (ref: Hoekstra doi.org/10.1016/j.ccell.2023.12.010/). Furthermore, Wienke et al. conducted a single-cell RNA sequencing analysis of neuroblastoma, identifying the NECTIN2-TIGIT axis as a potential target for immunotherapy, which underscores the utility of single-cell approaches in uncovering novel therapeutic targets (ref: Wienke doi.org/10.1016/j.ccell.2023.12.008/). The development of technologies like Decoder-seq, which enhances mRNA capture efficiency in spatial RNA sequencing, represents a significant advancement in the field, enabling more detailed mapping of cellular interactions within tumors (ref: Cao doi.org/10.1038/s41587-023-02086-y/). These studies collectively highlight the transformative potential of single-cell and spatial profiling in cancer research.

The extracellular matrix (ECM) and stromal components of the TME are critical in regulating tumor behavior and therapeutic responses. Mathur et al. highlighted the role of the ECM in glioblastoma, where 3D spatial mapping revealed significant intratumoral heterogeneity and its implications for treatment resistance (ref: Mathur doi.org/10.1016/j.cell.2023.12.013/). In small cell lung cancer, Liu et al. identified subtype-specific therapeutic strategies through proteogenomic characterization, emphasizing how ECM interactions can influence tumor biology and treatment outcomes (ref: Liu doi.org/10.1016/j.cell.2023.12.004/). Zhao et al. explored the potential of IL-10-expressing CAR T cells to resist dysfunction in the solid tumor microenvironment, demonstrating how stromal factors can impact T cell efficacy (ref: Zhao doi.org/10.1038/s41587-023-02060-8/). Additionally, Bejarano et al. investigated the role of endothelial and mural cells in brain metastasis, revealing their importance in immune regulation and tumor progression (ref: Bejarano doi.org/10.1016/j.ccell.2023.12.018/). These findings underscore the necessity of targeting ECM and stromal interactions to enhance therapeutic efficacy.

Tumor metabolism is intricately linked to immune evasion, with metabolic reprogramming enabling cancer cells to escape immune surveillance. Recent studies have focused on the metabolic adaptations of tumors and their impact on immune responses. Zhang et al. conducted a comprehensive analysis of microRNAs in hepatocellular carcinoma, identifying key metabolic pathways associated with sorafenib resistance and immune evasion (ref: Zhang doi.org/10.5306/wjco.v15.i1.145/). Wu et al. explored the prognostic and immunological roles of heat shock protein A4 in lung adenocarcinoma, revealing its correlation with immune infiltration and suggesting its potential as a therapeutic target (ref: Wu doi.org/10.5306/wjco.v15.i1.45/). Wang et al. investigated long noncoding RNAs associated with disulfidptosis in colorectal cancer, highlighting their role in immune response modulation and potential implications for immunotherapy (ref: Wang doi.org/10.5306/wjco.v15.i1.89/). Ng et al. demonstrated that neutrophils undergo deterministic reprogramming within tumors, which may contribute to poor clinical outcomes and immune evasion (ref: Ng doi.org/10.1126/science.adf6493/). These studies collectively illustrate the critical interplay between tumor metabolism and immune evasion, emphasizing the need for integrated therapeutic strategies.

The identification of effective therapeutic strategies and biomarkers is crucial for improving cancer treatment outcomes. Recent research has focused on integrating multi-omics approaches to uncover novel therapeutic targets and prognostic indicators. Liu et al. performed a comprehensive proteogenomic characterization of small cell lung cancer, identifying key oncogenic mutations and prognostic biomarkers that could guide treatment decisions (ref: Liu doi.org/10.1016/j.cell.2023.12.004/). Shiao et al. utilized single-cell and spatial profiling to analyze response trajectories in triple-negative breast cancer, providing insights into patient stratification for immunotherapy (ref: Shiao doi.org/10.1016/j.ccell.2023.12.012/). Additionally, Goddard et al. explored the immune evasion mechanisms of dormant disseminated tumor cells, suggesting that T cell immunotherapies could be a viable strategy to target these cells (ref: Goddard doi.org/10.1016/j.ccell.2023.12.011/). The phase 3 ZUMA-7 trial demonstrated the superiority of anti-CD19 CAR T cell therapy over standard care in large B cell lymphoma, highlighting the importance of biomarker-driven patient selection (ref: Locke doi.org/10.1038/s41591-023-02754-1/). These findings underscore the potential of personalized medicine approaches in optimizing therapeutic strategies.

Cancer stem cells (CSCs) and tumor heterogeneity are pivotal in tumor progression and treatment resistance. Mathur et al. emphasized the role of intratumoral heterogeneity in glioblastoma, revealing how 3D spatial mapping can uncover the complexities of tumor evolution and treatment failure (ref: Mathur doi.org/10.1016/j.cell.2023.12.013/). Liu et al. also contributed to this understanding through their proteogenomic analysis of small cell lung cancer, identifying key mutations and their implications for tumor heterogeneity and therapeutic strategies (ref: Liu doi.org/10.1016/j.cell.2023.12.004/). The study by Wienke et al. on neuroblastoma highlighted the immunoregulatory interactions within tumors, suggesting that targeting CSCs may enhance immunotherapy efficacy (ref: Wienke doi.org/10.1016/j.ccell.2023.12.008/). Furthermore, Zhao et al. demonstrated that IL-10-expressing CAR T cells can resist dysfunction in the TME, indicating a potential strategy to overcome the challenges posed by tumor heterogeneity (ref: Zhao doi.org/10.1038/s41587-023-02060-8/). These studies collectively underscore the importance of understanding CSCs and tumor heterogeneity in developing effective cancer therapies.

Clinical trials and translational research are essential for bridging the gap between laboratory findings and patient care. Memon et al. investigated acquired resistance to PD-(L)1 blockade in NSCLC, providing insights that could inform future clinical trial designs aimed at overcoming resistance mechanisms (ref: Memon doi.org/10.1016/j.ccell.2023.12.013/). Gavrielatou et al. focused on the role of B-cell infiltration in head and neck squamous cell carcinoma, identifying biomarkers that could predict patient responses to PD-1 inhibitors, thus enhancing patient selection in clinical trials (ref: Gavrielatou doi.org/10.1016/j.annonc.2023.12.011/). The ZUMA-7 trial demonstrated the efficacy of anti-CD19 CAR T cell therapy in large B cell lymphoma, highlighting the importance of biomarker-driven approaches in clinical settings (ref: Locke doi.org/10.1038/s41591-023-02754-1/). Additionally, Shiao et al. utilized single-cell and spatial profiling to analyze treatment responses in triple-negative breast cancer, emphasizing the potential for personalized treatment strategies based on tumor heterogeneity (ref: Shiao doi.org/10.1016/j.ccell.2023.12.012/). These studies collectively illustrate the critical role of clinical trials and translational research in advancing cancer therapies.