The tumor microenvironment (TME) plays a crucial role in cancer progression and metastasis, with recent studies highlighting the complex interplay between tumor cells and their surrounding stroma. Lucotti et al. demonstrated that small extracellular vesicles (sEVs) from CXCL13-reprogrammed interstitial macrophages in the lung create a pro-thrombotic niche that drives cancer-associated thrombosis and metastasis, particularly in pancreatic ductal adenocarcinoma (ref: Lucotti doi.org/10.1016/j.cell.2025.01.025/). Chen et al. utilized co-detection by indexing (CODEX) and multi-omics profiling to reveal significant tumor heterogeneity and immune colony niches in small cell lung cancer (SCLC), providing insights into spatial organization and cellular interactions that correlate with clinical outcomes (ref: Chen doi.org/10.1016/j.ccell.2025.01.012/). Furthermore, Zhang et al. explored the tumor immune microenvironment in triple-negative breast cancer (TNBC) and identified distinct cellular mechanisms underlying the efficacy of chemotherapy combined with PD-L1 blockade, emphasizing the importance of TCF7 reprogramming in response to treatment (ref: Zhang doi.org/10.1016/j.ccell.2025.01.007/). These findings collectively underscore the dynamic nature of the TME and its influence on therapeutic responses and cancer progression.

Recent advancements in immune modulation strategies have shown promise in enhancing therapeutic efficacy against various cancers. Nguyen et al. introduced a novel approach using engineered adipocytes to outcompete tumors for nutrients, demonstrating significant suppression of cancer progression through adipose manipulation transplantation (AMT) (ref: Nguyen doi.org/10.1038/s41587-024-02551-2/). In a phase 1 trial, Reiss et al. reported on CAR-macrophage therapy for HER2-overexpressing tumors, highlighting the potential of CAR-Ms to mediate antitumor immunity through phagocytosis and cytokine release (ref: Reiss doi.org/10.1038/s41591-025-03495-z/). Additionally, the study by Mavuluri et al. identified GPR65 inactivation in tumor cells as a key factor driving CAR T-cell resistance, suggesting that targeting macrophages and VEGFA could optimize CAR T-cell therapy outcomes (ref: Mavuluri doi.org/10.1158/2159-8290.CD-24-0841/). These studies illustrate the multifaceted strategies being explored to enhance immune responses and overcome resistance mechanisms in cancer therapy.

The extracellular matrix (ECM) is integral to tumor progression, influencing cellular behavior and metastatic potential. Fiore et al. developed a glycan-binding fluorophore, Rhobo6, enabling live imaging of ECM dynamics, which is crucial for understanding how ECM structure affects tumor biology (ref: Fiore doi.org/10.1038/s41592-024-02590-2/). Li et al. investigated the role of microbiome dysbiosis and mesothelial cell transition in promoting peritoneal metastasis of colorectal cancer, revealing that the tumor microenvironment significantly remodels to facilitate cancer progression (ref: Li doi.org/10.1038/s43018-025-00910-9/). Furthermore, Arnold et al. highlighted the role of DCLK1 in regulating invadopodia dynamics and matrix metalloproteinase trafficking, which is essential for invasive progression in head and neck squamous cell carcinoma (ref: Arnold doi.org/10.1186/s12943-025-02264-3/). Collectively, these findings emphasize the ECM's role in tumor behavior and the potential for targeting ECM components in therapeutic strategies.

Cancer cells exhibit altered metabolic pathways that enable them to thrive in nutrient-limited environments. Nguyen et al. demonstrated that engineered adipocytes can suppress tumor growth by competing for nutrients, particularly uridine, in pancreatic ductal adenocarcinoma models (ref: Nguyen doi.org/10.1038/s41587-024-02551-2/). Additionally, Rodriguez-Baena et al. identified mechanisms by which microglial reprogramming enhances antitumor immunity in melanoma brain metastases, suggesting that metabolic reprogramming within the tumor microenvironment can influence immune responses (ref: Rodriguez-Baena doi.org/10.1016/j.ccell.2025.01.008/). Li et al. further explored the transcriptional profiles associated with peritoneal metastasis in colorectal cancer, revealing key metabolic players that facilitate tumor progression (ref: Li doi.org/10.1038/s43018-025-00910-9/). These studies highlight the critical interplay between cancer metabolism and immune modulation, suggesting that targeting metabolic pathways may enhance therapeutic efficacy.

Tumor-associated inflammation is a double-edged sword that can promote tumor growth while simultaneously activating immune responses. Zhang et al. investigated the mechanisms underlying the combination of chemotherapy and PD-L1 blockade in triple-negative breast cancer, revealing that different therapeutic combinations can rewire the tumor immune microenvironment (ref: Zhang doi.org/10.1016/j.ccell.2025.01.007/). Rodriguez-Baena et al. also highlighted the role of microglial activation in enhancing antitumor immunity in melanoma brain metastases, suggesting that inflammatory signals can be harnessed to improve immunotherapy outcomes (ref: Rodriguez-Baena doi.org/10.1016/j.ccell.2025.01.008/). Conversely, Ma et al. demonstrated that tumor-derived extracellular vesicle PD-L1 promotes T cell senescence, indicating a mechanism of immune evasion that limits the effectiveness of immunotherapies (ref: Ma doi.org/10.1126/scitranslmed.adm7269/). These findings underscore the complexity of tumor-associated inflammation and its implications for therapeutic strategies.

Innovative therapeutic strategies are being developed and tested in clinical trials to improve cancer treatment outcomes. Dal Pra et al. validated a radiation signature in prostate cancer patients, demonstrating that specific biomarkers can predict treatment responses and guide personalized therapy (ref: Dal Pra doi.org/10.1016/j.annonc.2025.01.017/). In the phase 1 trial by Reiss et al., CAR-macrophage therapy showed promise in treating HER2-overexpressing tumors, indicating a novel approach to harnessing the immune system for cancer therapy (ref: Reiss doi.org/10.1038/s41591-025-03495-z/). Shen et al. evaluated the efficacy of combining apatinib with chemotherapy in early-stage triple-negative breast cancer, reporting encouraging results in achieving pathological complete response rates (ref: Shen doi.org/10.1038/s41392-025-02137-7/). These studies reflect the ongoing efforts to refine therapeutic modalities and enhance patient outcomes through targeted and personalized approaches.

Understanding tumor heterogeneity is essential for developing effective cancer therapies. Chen et al. employed integrative spatial analysis to reveal the complex immune landscape and tumor heterogeneity in small cell lung cancer, providing insights into how these factors relate to clinical outcomes (ref: Chen doi.org/10.1016/j.ccell.2025.01.012/). Zhang et al. further explored the tumor immune microenvironment in triple-negative breast cancer, utilizing single-cell RNA sequencing to dissect the cellular mechanisms that underlie treatment responses (ref: Zhang doi.org/10.1016/j.ccell.2025.01.007/). Additionally, Li et al. highlighted the transcriptional profiles associated with peritoneal metastasis in colorectal cancer, emphasizing the need for genomic profiling to understand tumor progression (ref: Li doi.org/10.1038/s43018-025-00910-9/). These findings underscore the importance of genomic profiling in elucidating tumor heterogeneity and guiding personalized treatment strategies.

Neuroimmune interactions are increasingly recognized as critical components of the tumor microenvironment. Li et al. demonstrated that sciatic nerve stimulation enhances NK cell cytotoxicity through dopamine signaling, suggesting a novel approach to augmenting immunotherapy in triple-negative breast cancer (ref: Li doi.org/10.1016/j.drup.2025.101212/). Additionally, the study by Nishinakamura et al. revealed mechanisms of acquired resistance to combined TLR agonism and PD-1 blockade, highlighting the complexity of immune responses in the presence of neuroimmune interactions (ref: Nishinakamura doi.org/10.1126/scitranslmed.adk3160/). These findings indicate that understanding the interplay between the nervous system and immune responses may provide new avenues for therapeutic interventions in cancer.