The tumor microenvironment (TME) plays a crucial role in cancer progression and therapeutic responses. Recent studies have highlighted the complex interactions between cancer cells and stromal components, particularly focusing on immune and metabolic dynamics. For instance, Westfall et al. demonstrated that type 1 immune-stromal cell networks are essential for mediating disease tolerance against intestinal infections, suggesting that IFNγ signaling can limit tissue damage and maintain gut motility during infections (ref: Westfall doi.org/10.1016/j.cell.2025.03.043/). In melanoma, Gurung et al. found that stromal lipid species from adipocytes significantly influence cancer cell metabolism, promoting PI3K-AKT signaling and oxidative phosphorylation, which in turn affects metastatic tropism (ref: Gurung doi.org/10.1016/j.ccell.2025.04.001/). Zhu et al. further explored metabolic interactions, revealing that arginine derived from cancer cells fuels polyamine biosynthesis in tumor-associated macrophages, thereby enhancing immune evasion (ref: Zhu doi.org/10.1016/j.ccell.2025.03.015/). These findings collectively underscore the importance of metabolic reprogramming and immune interactions in shaping the TME and influencing cancer outcomes. Moreover, the spatial organization of immune structures within tumors has been investigated by Tang et al., who utilized spatial transcriptomics to reveal how tryptophan metabolism restricts the maturation of tertiary lymphoid structures (TLSs) in hepatocellular carcinoma (ref: Tang doi.org/10.1016/j.ccell.2025.03.011/). The presence of TLSs is often associated with improved immunotherapy responses, indicating that understanding their maturation could enhance therapeutic strategies. Additionally, the safety and efficacy of adoptive cell therapies, particularly with tumor-infiltrating lymphocytes (TILs), have been systematically reviewed by Martín-Lluesma et al., emphasizing the need for careful management of treatment-related adverse events (ref: Martín-Lluesma doi.org/10.1016/j.annonc.2025.04.001/). Overall, these studies illustrate the multifaceted nature of the TME and its critical influence on cancer progression and treatment responses.

Immune evasion remains a significant barrier to effective cancer treatment, with various mechanisms employed by tumors to escape immune surveillance. Gao et al. highlighted the role of hypoxia-induced phase separation of ZHX2, which alters chromatin looping to activate oncogenic transcription, thereby promoting metastasis in breast cancer (ref: Gao doi.org/10.1016/j.molcel.2025.03.009/). This finding suggests that hypoxic conditions within tumors can facilitate immune evasion by enhancing the expression of genes associated with malignancy. In a complementary study, Guilbaud et al. demonstrated that a short IL18 cleavage product can promote cancer immunosurveillance, indicating that manipulating cytokine processing may enhance anti-tumor immunity (ref: Guilbaud doi.org/10.1038/s41392-025-02213-y/). Cheng et al. provided insights into how bone metastases can diminish the efficacy of immune checkpoint blockade therapies through osteopontin-producing osteoclasts, revealing a mechanism of long-distance communication that induces resistance in extraosseous tumors (ref: Cheng doi.org/10.1016/j.ccell.2025.03.036/). This highlights the systemic nature of immune evasion and the need to consider the entire tumor microenvironment when developing therapeutic strategies. Additionally, the study by Cifuentes et al. on the R-RAS2 GTPase emphasized its role as a signaling hub in triple-negative breast cancer, further complicating the landscape of immune evasion (ref: Cifuentes doi.org/10.1186/s13045-025-01693-3/). Collectively, these studies illustrate the diverse strategies tumors employ to evade immune detection and the potential for targeted interventions to overcome these barriers.

Tumor-associated macrophages (TAMs) play a pivotal role in shaping the immune landscape of tumors and influencing the efficacy of immunotherapies. Recent research has focused on the metabolic interactions between TAMs and cancer cells, with Zhu et al. revealing that arginine metabolism from cancer cells fuels polyamine biosynthesis in macrophages, promoting immune evasion (ref: Zhu doi.org/10.1016/j.ccell.2025.03.015/). This metabolic cross-talk highlights the importance of targeting metabolic pathways to enhance the effectiveness of immunotherapies. Furthermore, the study by Tang et al. on the maturation of tertiary lymphoid structures (TLSs) in hepatocellular carcinoma underscores the significance of macrophage interactions in fostering an immune-supportive environment (ref: Tang doi.org/10.1016/j.ccell.2025.03.011/). The safety and efficacy of adoptive cell therapies, particularly using tumor-infiltrating lymphocytes (TILs), have been systematically reviewed by Martín-Lluesma et al., emphasizing the need for careful management of treatment-related adverse events (ref: Martín-Lluesma doi.org/10.1016/j.annonc.2025.04.001/). This review highlights the potential of TILs in overcoming immune suppression mediated by TAMs. Additionally, the findings by Gurung et al. regarding the impact of stromal lipid species on melanoma metastasis further illustrate the interplay between TAMs and the tumor microenvironment, suggesting that targeting these interactions could enhance therapeutic outcomes (ref: Gurung doi.org/10.1016/j.ccell.2025.04.001/). Overall, these studies emphasize the critical role of TAMs in cancer progression and the potential for innovative therapeutic strategies to modulate their function.

Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to their microenvironment and support rapid growth and survival. Zhu et al. explored how arginine metabolism from cancer cells fuels polyamine biosynthesis in tumor-associated macrophages, promoting immune evasion and highlighting the metabolic interplay between these cell types (ref: Zhu doi.org/10.1016/j.ccell.2025.03.015/). This study underscores the importance of understanding metabolic pathways in the context of tumor-immune interactions, suggesting that targeting these pathways could enhance therapeutic efficacy. Gurung et al. further investigated the role of stromal lipid species in melanoma metastasis, demonstrating that lipids from adipocytes are taken up by melanoma cells, leading to enhanced PI3K-AKT signaling and oxidative phosphorylation (OXPHOS) (ref: Gurung doi.org/10.1016/j.ccell.2025.04.001/). Their findings indicate that metabolic adaptations not only support tumor growth but also influence metastatic behavior, with high OXPHOS melanoma cells showing a preference for seeding in specific organs. Additionally, the safety and efficacy of adoptive cell therapies, particularly with TILs, have been reviewed by Martín-Lluesma et al., emphasizing the need for careful management of treatment-related adverse events (ref: Martín-Lluesma doi.org/10.1016/j.annonc.2025.04.001/). Collectively, these studies highlight the critical role of metabolic reprogramming in cancer and its implications for therapeutic strategies.

Hypoxia is a common feature of the tumor microenvironment that significantly influences tumor progression and therapeutic responses. Gao et al. demonstrated that hypoxia-induced phase separation of ZHX2 alters chromatin looping, promoting the transcription of oncogenes and facilitating metastasis in breast cancer (ref: Gao doi.org/10.1016/j.molcel.2025.03.009/). This finding suggests that hypoxic conditions can enhance the malignant potential of tumors by modifying gene expression patterns. Furthermore, the study by Cheng et al. revealed that bone metastases can diminish the efficacy of immune checkpoint blockade therapies through osteopontin-producing osteoclasts, indicating that hypoxic conditions in the bone microenvironment may contribute to immune evasion (ref: Cheng doi.org/10.1016/j.ccell.2025.03.036/). Additionally, the research by Cifuentes et al. on the R-RAS2 GTPase highlighted its role as a signaling hub in triple-negative breast cancer, further complicating the relationship between hypoxia and tumor progression (ref: Cifuentes doi.org/10.1186/s13045-025-01693-3/). The interplay between hypoxia, metabolic reprogramming, and immune evasion underscores the need for integrated therapeutic approaches that target these interconnected pathways. Overall, these studies emphasize the critical role of hypoxia in shaping tumor behavior and the potential for novel therapeutic strategies to overcome its effects.

Cancer cell heterogeneity and evolution are critical factors that influence tumor behavior and treatment responses. Recent studies have focused on the metabolic interactions and immune evasion strategies employed by heterogeneous tumor populations. Zhu et al. highlighted how arginine metabolism from cancer cells fuels polyamine biosynthesis in tumor-associated macrophages, promoting immune evasion and suggesting that metabolic cross-talk is a key driver of tumor heterogeneity (ref: Zhu doi.org/10.1016/j.ccell.2025.03.015/). This finding underscores the importance of understanding the metabolic landscape of tumors to develop effective therapeutic strategies. Gurung et al. further explored the role of stromal lipid species in melanoma metastasis, demonstrating that these lipids can influence cancer cell metabolism and metastatic behavior (ref: Gurung doi.org/10.1016/j.ccell.2025.04.001/). Their study indicates that the metabolic adaptations of cancer cells are not only a response to intrinsic factors but also to the surrounding microenvironment, contributing to the evolutionary dynamics of tumors. Additionally, the safety and efficacy of adoptive cell therapies, particularly with TILs, have been reviewed by Martín-Lluesma et al., emphasizing the need for careful management of treatment-related adverse events in heterogeneous tumor populations (ref: Martín-Lluesma doi.org/10.1016/j.annonc.2025.04.001/). Collectively, these studies highlight the complex interplay between cancer cell heterogeneity, metabolic reprogramming, and immune evasion, underscoring the need for innovative therapeutic approaches that consider these factors.

Innovative therapeutic strategies are essential for improving cancer treatment outcomes, particularly in the context of immune evasion and tumor heterogeneity. Martín-Lluesma et al. conducted a systematic review on the safety and efficacy of adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs), highlighting the potential of this approach in advanced melanoma while also addressing the challenges associated with treatment-related adverse events (ref: Martín-Lluesma doi.org/10.1016/j.annonc.2025.04.001/). This review emphasizes the importance of optimizing treatment protocols to enhance patient safety and therapeutic efficacy. Additionally, Zhu et al. explored the metabolic interplay between cancer cells and tumor-associated macrophages, revealing how arginine metabolism can promote immune evasion (ref: Zhu doi.org/10.1016/j.ccell.2025.03.015/). This finding suggests that targeting metabolic pathways could enhance the effectiveness of immunotherapies. Gurung et al. further investigated the role of stromal lipid species in melanoma metastasis, demonstrating that these lipids can influence cancer cell behavior and therapeutic responses (ref: Gurung doi.org/10.1016/j.ccell.2025.04.001/). Their work indicates that understanding the metabolic context of tumors is crucial for developing effective therapeutic strategies. Moreover, the research by Cheng et al. on the impact of bone metastases on immune checkpoint blockade therapies highlights the need for innovative approaches to overcome resistance mechanisms (ref: Cheng doi.org/10.1016/j.ccell.2025.03.036/). Overall, these studies underscore the importance of integrating novel therapeutic strategies with a comprehensive understanding of tumor biology to improve cancer treatment outcomes.

The extracellular matrix (ECM) plays a vital role in tumor progression and the interaction between cancer cells and their microenvironment. Zhu et al. investigated how cancer cell-derived arginine influences the metabolic landscape of tumor-associated macrophages, promoting immune evasion and highlighting the importance of ECM components in shaping tumor-immune interactions (ref: Zhu doi.org/10.1016/j.ccell.2025.03.015/). This study emphasizes the need to consider the ECM's role in metabolic reprogramming and immune modulation within the tumor microenvironment. Gurung et al. further explored the impact of stromal lipid species on melanoma metastasis, demonstrating that these lipids can significantly influence cancer cell behavior and therapeutic responses (ref: Gurung doi.org/10.1016/j.ccell.2025.04.001/). Their findings suggest that the ECM not only provides structural support but also actively participates in metabolic signaling that affects tumor progression. Additionally, Martín-Lluesma et al. conducted a systematic review on the safety and efficacy of adoptive cell therapy (ACT) with TILs, emphasizing the need for careful management of treatment-related adverse events in the context of ECM interactions (ref: Martín-Lluesma doi.org/10.1016/j.annonc.2025.04.001/). Collectively, these studies highlight the critical role of the ECM in tumor biology and its potential as a therapeutic target.