The tumor microenvironment (TME) plays a critical role in shaping the immune response to cancer therapies, particularly immunotherapies. A study utilizing single-cell RNA and TCR sequencing analyzed surgical samples from 234 non-small cell lung cancer (NSCLC) patients treated with anti-PD-1 therapy, revealing significant immune heterogeneity that correlates with variable therapeutic outcomes (ref: Liu doi.org/10.1016/j.cell.2025.03.018/). This highlights the importance of understanding the TME's composition and its influence on treatment efficacy. Another study focused on clear cell renal cell carcinoma (ccRCC) demonstrated that hypoxia-induced upregulation of the HIF transcription factor activates endogenous retroviruses, which may enhance immune recognition and response to therapies (ref: Jiang doi.org/10.1016/j.cell.2025.01.046/). Furthermore, research on bacterial immunotherapy indicated that engineered Salmonella can evade immune defenses while simultaneously stimulating anti-tumor responses, showcasing a novel approach to harnessing the TME for therapeutic benefit (ref: Chang doi.org/10.1016/j.cell.2025.02.002/). Together, these studies underscore the complexity of immune interactions within the TME and their implications for improving cancer treatment strategies. In addition to immune modulation, the TME's metabolic landscape significantly influences tumor behavior and treatment resistance. For instance, a study on triple-negative breast cancer (TNBC) identified that tumor-derived arachidonic acid reprograms neutrophils, promoting immune suppression and therapy resistance (ref: Yu doi.org/10.1016/j.immuni.2025.03.002/). This finding emphasizes the need to explore metabolic pathways as potential therapeutic targets. Moreover, anti-VEGF treatment was shown to enhance the efficacy of immune checkpoint blockade through a BAFF- and IL-12-dependent mechanism, indicating that targeting the TME can synergistically improve immunotherapy outcomes (ref: Benmebarek doi.org/10.1016/j.immuni.2025.02.017/). Lastly, the characterization of cancer-associated fibroblasts (CAFs) through single-cell spatial multi-omics revealed distinct spatial subtypes that contribute to the TME's complexity and influence therapy responses (ref: Liu doi.org/10.1016/j.ccell.2025.03.004/). These insights collectively highlight the multifaceted interactions within the TME that dictate tumor progression and therapeutic responses.

Cancer-associated fibroblasts (CAFs) are pivotal in modulating the tumor microenvironment (TME) and influencing cancer progression and treatment responses. A comprehensive study utilizing single-cell spatial multi-omics analyzed over 14 million cells from various cancer types, identifying four distinct spatial subtypes of CAFs that exhibit unique cellular neighborhoods and interactions within the TME (ref: Liu doi.org/10.1016/j.ccell.2025.03.004/). This research underscores the importance of spatial organization in understanding CAF functionality and their role in shaping the immune landscape of tumors. Additionally, a clinical trial comparing neoadjuvant anti-PD-1 therapies in head and neck squamous cell carcinoma revealed that combination therapies significantly enhance pathologic response rates, suggesting that CAFs may play a role in mediating these responses through their interactions with immune cells (ref: Li doi.org/10.1016/j.ccell.2025.02.026/). Moreover, the interaction between neutrophils and tumor cells was explored, revealing that neutrophils form a signaling niche that promotes breast cancer aggressiveness (ref: Camargo doi.org/10.1038/s43018-025-00924-3/). This highlights the dynamic interplay between different cell types within the TME and their collective impact on tumor behavior. Another study demonstrated that CAFs can suppress natural killer (NK) cell activity, acting as decoys that inhibit anticancer immunity in breast cancer (ref: Ben-Shmuel doi.org/10.1158/2159-8290.CD-24-0131/). This finding emphasizes the need to consider CAFs as critical players in the immune evasion strategies of tumors. Furthermore, the role of nociceptor neurons in pancreatic ductal adenocarcinoma (PDAC) was investigated, revealing that these neurons interact with CAFs to promote tumor progression and suppress NK cell activity (ref: Wang doi.org/10.1038/s41422-025-01098-4/). Collectively, these studies illustrate the multifaceted roles of CAFs and stromal dynamics in influencing tumor biology and therapeutic responses.

Therapeutic resistance remains a significant challenge in cancer treatment, particularly in the context of immunotherapy. A study on non-small cell lung cancer (NSCLC) patients treated with anti-PD-1 therapy revealed substantial immune heterogeneity within the tumor microenvironment (TME), which correlated with varying patient responses to treatment (ref: Liu doi.org/10.1016/j.cell.2025.03.018/). This highlights the necessity for personalized approaches in immunotherapy, as understanding the TME's composition can inform treatment strategies. Additionally, a phase II trial investigating the combination of anti-PDL1 therapy with stereotactic body radiation therapy (SBRT) in soft-tissue sarcoma patients found that monocyte-lineage tumor infiltration could predict treatment response, suggesting that immune cell dynamics are critical for therapeutic efficacy (ref: Levy doi.org/10.1038/s41392-025-02173-3/). In the context of overcoming resistance, a novel small molecule targeting RNA structure was shown to repress tumorigenesis in castration-resistant prostate cancer (CRPC) models, indicating that targeting specific molecular vulnerabilities can enhance treatment outcomes (ref: Kuzuoglu-Ozturk doi.org/10.1016/j.ccell.2025.02.027/). Furthermore, the use of a TIM-3-Fc decoy secreted by engineered T cells improved the efficacy of CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia, demonstrating the potential of modifying immune checkpoints to enhance therapeutic responses (ref: Falgàs doi.org/10.1182/blood.2024025440/). Additionally, targeting TRAP1-dependent metabolic reprogramming was found to overcome doxorubicin resistance in quiescent breast cancer cells, suggesting that metabolic pathways are critical in mediating therapeutic resistance (ref: Saleem doi.org/10.1016/j.drup.2025.101226/). These findings collectively underscore the complexity of therapeutic resistance mechanisms and the need for innovative strategies to enhance the efficacy of immunotherapies.

Spatial omics technologies have revolutionized our understanding of tumor heterogeneity by enabling the characterization of cellular interactions within the tumor microenvironment (TME). A study mapping the spatial evolution of esophageal carcinogenesis at single-cell resolution revealed that a proliferative epithelial cell subpopulation drives tumor progression, highlighting the dynamic interplay between cancer cells and their microenvironment (ref: Chang doi.org/10.1016/j.ccell.2025.02.009/). This research emphasizes the importance of spatial context in understanding tumor evolution and the potential for spatially targeted therapies. Furthermore, the development of NicheCompass, a graph deep-learning method, allows for the identification and characterization of cellular niches based on spatial omics data, enhancing our ability to decipher complex cellular interactions within tissues (ref: Birk doi.org/10.1038/s41588-025-02120-6/). Additionally, a study investigating the role of GOLPH3L in glioblastoma demonstrated that targeting this protein can improve radiotherapy outcomes by reprogramming the TME, indicating that spatially resolved omics can inform therapeutic strategies (ref: Sun doi.org/10.1126/scitranslmed.ado0020/). Another innovative approach, SIMVI, was introduced to disentangle intrinsic and spatial-induced cellular states in spatial omics data, providing a more nuanced understanding of cellular behavior in the TME (ref: Dong doi.org/10.1038/s41467-025-58089-7/). Collectively, these studies highlight the transformative potential of spatial omics in elucidating tumor heterogeneity and guiding personalized therapeutic interventions.

The extracellular matrix (ECM) plays a crucial role in modulating cellular behavior and tumor progression through mechanical and biochemical signals. A study investigating the effects of tension anisotropy on fibroblast phenotypic transitions revealed that stress fields experienced by cells are critical in determining their fate, with anisotropic stress being a more significant factor than stress amplitude (ref: Alisafaei doi.org/10.1038/s41563-025-02162-5/). This finding underscores the importance of mechanical properties in shaping the tumor microenvironment and influencing cellular responses. Additionally, a novel self-oxygenating PROTAC microneedle system was developed for glioblastoma therapy, integrating dual-activatable nanoparticles to enhance therapeutic efficacy while addressing the challenges posed by the blood-brain barrier (ref: Jiang doi.org/10.1002/adma.202411869/). Moreover, the characterization of endothelial and mural cells across primary and metastatic brain tumors provided insights into the blood-brain barrier's role in tumor biology, revealing distinct cellular behaviors in different tumor contexts (ref: Bejarano doi.org/10.1016/j.immuni.2025.02.022/). Another study demonstrated that anti-TGF-β/PD-L1 bispecific antibodies can synergize with radiotherapy to enhance antitumor immunity while mitigating radiation-induced pulmonary fibrosis, highlighting the potential for targeting ECM components to improve therapeutic outcomes (ref: Wu doi.org/10.1186/s13045-025-01678-2/). These findings collectively emphasize the critical role of the ECM and mechanical properties in influencing tumor dynamics and therapeutic responses.

Tumor metabolism is intricately linked to immune evasion, with cancer cells often reprogramming their metabolic pathways to escape immune surveillance. A study revealed that hypoxia-induced phosphorylation of PCK1 inhibits cGAS-STING activation, promoting immune evasion in tumors (ref: Qin doi.org/10.1084/jem.20240902/). This highlights the metabolic adaptations that tumors undergo to suppress immune responses, suggesting that targeting metabolic pathways could enhance the efficacy of immunotherapies. Additionally, activated T cells were shown to reeducate tumor-associated macrophages (TAMs), breaking the tumor immunosuppressive environment through a prostaglandin D2 autocrine loop (ref: Trotta doi.org/10.1158/2159-8290.CD-24-0415/). This finding underscores the potential for leveraging T cell activation to modulate the immune landscape in tumors. Furthermore, a study on the gut microbiome's influence on primary central nervous system lymphoma patients undergoing chemotherapy indicated that specific microbiota compositions could correlate with treatment outcomes, suggesting that the microbiome may play a role in modulating tumor metabolism and immune responses (ref: Hernández-Verdin doi.org/10.1093/neuonc/). Moreover, neutrophils were found to interact with tumor cells, forming a signaling niche that promotes breast cancer aggressiveness, further illustrating the complex interplay between metabolism and immune dynamics in the TME (ref: Camargo doi.org/10.1038/s43018-025-00924-3/). Collectively, these studies highlight the critical role of tumor metabolism in immune evasion and the potential for targeting metabolic pathways to enhance therapeutic efficacy.

Endothelial cells play a pivotal role in tumor vascular dynamics, influencing tumor growth and metastasis. A comprehensive analysis of endothelial and mural cells across various brain tumors revealed distinct cellular behaviors and interactions that contribute to the integrity of the blood-brain barrier (BBB) and tumor progression (ref: Bejarano doi.org/10.1016/j.immuni.2025.02.022/). This study emphasizes the importance of understanding endothelial cell dynamics in the context of both primary and metastatic brain tumors, as alterations in these cells can significantly impact treatment responses. Furthermore, the investigation of ultra-high dose rate radiotherapy demonstrated its potential to overcome radioresistance in head and neck squamous cell carcinoma, suggesting that vascular dynamics may play a role in mediating therapeutic efficacy (ref: Li doi.org/10.1038/s41392-025-02184-0/). Additionally, a study on renal cell carcinoma identified determinants of late metastases, revealing that clear cell histology and favorable histopathological features are associated with delayed metastatic onset (ref: Kapur doi.org/10.1093/jnci/). This finding highlights the need for further exploration of endothelial cell interactions in the metastatic process. Moreover, the development of in situ valence-transited arsenic nanosheets for colorectal cancer therapy illustrates the potential for targeting vascular dynamics to enhance treatment efficacy in advanced disease stages (ref: Zheng doi.org/10.1038/s41467-025-57376-7/). Collectively, these studies underscore the critical role of endothelial cells in shaping the tumor microenvironment and their implications for therapeutic strategies.

Neuroimmune interactions are increasingly recognized as critical components of tumor biology, influencing cancer progression and therapeutic responses. A study on pancreatic ductal adenocarcinoma (PDAC) demonstrated that nociceptor neurons interact with cancer-associated fibroblasts (CAFs) to promote tumor progression and suppress natural killer (NK) cell activity, highlighting the role of the nervous system in modulating the TME (ref: Wang doi.org/10.1038/s41422-025-01098-4/). This finding underscores the importance of understanding neuroimmune dynamics in cancer, as they may offer new therapeutic targets for enhancing anti-tumor immunity. Additionally, a study investigating the gut microbiome's impact on primary central nervous system lymphoma patients undergoing chemotherapy found that specific microbiota compositions could correlate with treatment outcomes, suggesting that the microbiome may influence neuroimmune interactions (ref: Hernández-Verdin doi.org/10.1093/neuonc/). Moreover, the characterization of TIM-3 expression in T cells and its ligand in leukemic blasts revealed a correlation with clinical outcomes in B-cell acute lymphoblastic leukemia, indicating that neuroimmune interactions may also play a role in hematological malignancies (ref: Falgàs doi.org/10.1182/blood.2024025440/). These studies collectively highlight the complex interplay between the nervous system and immune responses in cancer, suggesting that targeting neuroimmune interactions could provide novel therapeutic strategies to improve patient outcomes.