The tumor microenvironment (TME) plays a critical role in cancer progression and immune evasion. Recent studies have highlighted various mechanisms through which tumors manipulate their surroundings to escape immune surveillance. For instance, Zhang et al. demonstrated that cancer cells in head and neck squamous cell carcinoma secrete slit guidance ligand 2 (SLIT2) under immune pressure, activating nociceptive neurons and remodeling tumor-draining lymph nodes into an immune-suppressed state (ref: Zhang doi.org/10.1016/j.cell.2025.09.029/). This finding underscores the importance of neuroimmune interactions in the TME. Additionally, Zhao et al. identified that tumor-associated macrophages (TAMs) maintain mitochondrial activity to support immunosuppression, with the mitochondrial chaperone TRAP1 acting as a metabolic checkpoint that limits macrophage function (ref: Zhao doi.org/10.1038/s41590-025-02324-2/). These studies collectively illustrate how tumors exploit both neuronal and immune components to foster an environment conducive to their survival. Moreover, the role of specific antigens in immune evasion has been explored, with Varkey et al. highlighting B cell maturation antigen (BCMA) as a promising target for immunotherapy in acute myeloid leukemia (AML) due to its restricted expression on malignant cells (ref: Varkey doi.org/10.1186/s13045-025-01741-y/). This suggests that targeting specific markers can potentially enhance therapeutic efficacy. Furthermore, Chen et al. utilized single-cell RNA sequencing to reveal a tumor-enriched subpopulation of inflammatory cancer-associated fibroblasts in cervical cancer, emphasizing the complexity of stroma-immune crosstalk in the TME (ref: Chen doi.org/10.1186/s12943-025-02471-y/). Together, these findings highlight the multifaceted interactions within the TME that contribute to immune evasion and suggest potential avenues for therapeutic intervention.

Immunotherapy has emerged as a cornerstone in cancer treatment, with various strategies being explored to enhance efficacy and safety. Ludin et al. identified CRATER tumor niches in melanoma, which facilitate CD8 T cell-mediated tumor killing, suggesting that targeting these niches could improve immunotherapy outcomes (ref: Ludin doi.org/10.1016/j.cell.2025.09.021/). This study emphasizes the importance of spatial dynamics in the tumor microenvironment for effective immune responses. In a different approach, the RELATIVITY-098 trial compared nivolumab plus relatlimab to nivolumab alone in advanced melanoma, demonstrating improved efficacy with the combination therapy (ref: Long doi.org/10.1038/s41591-025-04032-8/). This highlights the potential of combining immune checkpoint inhibitors to enhance therapeutic outcomes. Furthermore, the long-term safety and efficacy of gene therapy for adenosine deaminase deficiency were evaluated, showing a 100% overall survival rate among treated patients (ref: Booth doi.org/10.1056/NEJMoa2502754/). This underscores the promise of gene therapy as a viable immunotherapeutic strategy. In the realm of bladder cancer, Powles et al. reported significant improvements in disease-free and overall survival with ctDNA-guided adjuvant atezolizumab compared to placebo, reinforcing the role of precision medicine in immunotherapy (ref: Powles doi.org/10.1056/NEJMoa2511885/). Collectively, these studies illustrate the diverse strategies being employed in immunotherapy, from spatial targeting to genetic interventions, and their potential to reshape cancer treatment paradigms.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic malignancies, but its application in solid tumors remains challenging. Liu et al. introduced a tumor-on-a-chip model that allows for the study of CAR-T cell interactions within a vascularized tumor microenvironment, providing insights into enhancing CAR-T cell efficacy in solid tumors (ref: Liu doi.org/10.1038/s41587-025-02845-z/). This innovative approach could facilitate the identification of therapeutic targets that improve CAR-T cell performance. Additionally, Di Meo et al. explored the potential of targeting SEMA4A in multiple myeloma, revealing that this approach could overcome resistance associated with low BCMA expression (ref: Di Meo doi.org/10.1016/j.ccell.2025.09.007/). This finding highlights the need for alternative targets in CAR-T cell therapy to address relapse in patients. Moreover, Rotiroti et al. developed a platform that enhances CAR T cell sensitivity to low antigen levels by incorporating a membrane-tethered version of SLP-76, which could significantly improve the efficacy of CAR T cells against antigen-low tumors (ref: Rotiroti doi.org/10.1038/s43018-025-01056-4/). This advancement addresses a critical barrier in CAR T cell therapy, emphasizing the importance of innovative engineering strategies. Overall, these studies reflect a concerted effort to refine CAR-T cell therapy through novel engineering approaches and alternative targeting strategies, paving the way for more effective treatments in solid tumors.

The identification of biomarkers and predictive models is crucial for optimizing cancer treatment strategies. Pei et al. utilized single-cell multi-omics to uncover the immunosuppressive role of GPR116 in esophageal squamous cell carcinoma, providing insights into potential therapeutic targets (ref: Pei doi.org/10.1038/s41588-025-02341-9/). This study exemplifies the power of advanced profiling techniques in elucidating tumor biology and identifying actionable biomarkers. Furthermore, Yang et al. demonstrated that circulating tumor DNA (ctDNA) can refine consolidation immunotherapy for limited-stage small cell lung cancer, highlighting its potential as a dynamic prognostic tool (ref: Yang doi.org/10.1038/s41392-025-02445-y/). This underscores the importance of integrating biomarkers into treatment decision-making processes. In addition, the ALBAN trial investigated the combination of atezolizumab and Bacillus Calmette-Guérin (BCG) in high-risk non-muscle-invasive bladder cancer, aiming to identify predictive markers associated with treatment response (ref: Roupret doi.org/10.1016/j.annonc.2025.09.017/). This trial reflects the ongoing efforts to enhance the efficacy of existing therapies through biomarker-driven approaches. Lastly, Padilla et al. focused on lipid nanoparticle properties, emphasizing the need for precise characterization methods to improve drug delivery systems in cancer therapy (ref: Padilla doi.org/10.1038/s41587-025-02855-x/). Collectively, these studies highlight the critical role of biomarkers and predictive models in advancing personalized cancer treatment.

Gene therapy and genetic engineering are at the forefront of innovative cancer treatments, offering new avenues for addressing genetic disorders and malignancies. Booth et al. reported on the long-term safety and efficacy of lentiviral gene therapy for adenosine deaminase deficiency, achieving a 100% overall survival rate among treated patients (ref: Booth doi.org/10.1056/NEJMoa2502754/). This study underscores the potential of gene therapy to provide durable solutions for life-threatening conditions. Additionally, Goudy et al. developed an all-RNA platform for epigenetic programming in primary human T cells, allowing for precise control of gene expression without the risks associated with traditional genetic editing methods (ref: Goudy doi.org/10.1038/s41587-025-02856-w/). This advancement could enhance the safety and efficacy of T cell therapies. Moreover, the study by Zhang et al. revealed how cancer cells exploit neuroimmune circuits to evade immune surveillance, highlighting the complex interplay between genetic factors and the tumor microenvironment (ref: Zhang doi.org/10.1016/j.cell.2025.09.029/). This finding emphasizes the need for comprehensive approaches that integrate genetic insights with therapeutic strategies. Furthermore, the investigation of zanzalintinib plus atezolizumab in colorectal cancer demonstrated the potential of combining targeted therapies with immunotherapy to improve patient outcomes (ref: Hecht doi.org/10.1016/S0140-6736(25)02025-2/). Together, these studies illustrate the transformative potential of gene therapy and genetic engineering in cancer treatment, paving the way for innovative therapeutic strategies.

Combination therapies are increasingly recognized as a strategy to enhance the efficacy of cancer treatments. Sheng et al. reported that the combination of disitamab vedotin and toripalimab significantly improved outcomes in patients with HER2-expressing advanced urothelial cancer compared to chemotherapy alone (ref: Sheng doi.org/10.1056/NEJMoa2511648/). This finding underscores the potential of dual-targeting approaches in improving treatment responses. Similarly, the neoadjuvant treatment of IBI310 plus sintilimab in locally advanced MSI-H/dMMR colon cancer demonstrated promising efficacy, although the benefits of dual immune checkpoint inhibition over monotherapy remain to be fully elucidated (ref: Wang doi.org/10.1016/j.ccell.2025.09.004/). In the context of renal cell carcinoma, Hahn et al. conducted a phase II trial comparing lenvatinib plus everolimus to cabozantinib, revealing a higher objective response rate with the combination therapy (ref: Hahn doi.org/10.1016/j.annonc.2025.10.009/). This highlights the importance of exploring novel combinations to overcome resistance mechanisms in cancer treatment. Furthermore, Meng et al. proposed a dual-functional RNA-based strategy to enhance MHC-Class-I antigen presentation in hepatocellular carcinoma, addressing the challenge of immune evasion (ref: Meng doi.org/10.1186/s12943-025-02480-x/). Collectively, these studies illustrate the potential of combination therapies and novel agents in improving cancer treatment outcomes and addressing the complexities of tumor biology.

Tumor-associated macrophages (TAMs) play a pivotal role in shaping the immune landscape of tumors and influencing treatment outcomes. Zhao et al. identified that TAMs maintain mitochondrial activity in the nutrient-limited tumor microenvironment, which supports their immunosuppressive functions (ref: Zhao doi.org/10.1038/s41590-025-02324-2/). This finding highlights the metabolic adaptations of TAMs that contribute to immune evasion. Additionally, Varkey et al. demonstrated that B cell maturation antigen (BCMA) is a relevant target for immunotherapy in acute myeloid leukemia, suggesting that targeting specific antigens on TAMs could enhance therapeutic efficacy (ref: Varkey doi.org/10.1186/s13045-025-01741-y/). Moreover, Chen et al. utilized single-cell RNA sequencing to uncover a tumor-enriched subpopulation of inflammatory cancer-associated fibroblasts in cervical cancer, emphasizing the complex interactions between TAMs and the tumor microenvironment (ref: Chen doi.org/10.1186/s12943-025-02471-y/). This study illustrates the importance of understanding the cellular heterogeneity within tumors to develop effective immunotherapies. Furthermore, Dubey et al. revealed that glioblastoma induces alterations in the immune landscape of skull marrow, highlighting the systemic effects of tumors on immune cell dynamics (ref: Dubey doi.org/10.1038/s41593-025-02064-4/). Together, these findings underscore the critical role of TAMs in tumor biology and their potential as therapeutic targets for enhancing anti-tumor immunity.

Emerging therapeutic targets in cancer are crucial for developing novel treatment strategies. Sandén et al. identified SLAMF6 as a targetable immune escape mechanism in acute myeloid leukemia, demonstrating that its knockout enhances T cell activation and leukemia cell killing (ref: Sandén doi.org/10.1038/s43018-025-01054-6/). This finding highlights the potential of targeting immune checkpoints to improve therapeutic outcomes. Additionally, Hu et al. developed a scalable method for generating CAR-natural killer (NK) cells, which could provide a promising alternative to CAR-T cell therapies (ref: Hu doi.org/10.1038/s41551-025-01522-5/). This innovation addresses the need for efficient production of immune cells for therapy. Furthermore, Fazio et al. discussed the challenges in managing high-grade gastroenteropancreatic neuroendocrine neoplasms, emphasizing the need for novel therapeutic approaches in this complex disease (ref: Fazio doi.org/10.1210/endrev/). This highlights the ongoing efforts to identify and target specific pathways in cancer treatment. Lastly, Li et al. presented a microemulsion method for constructing diverse calcium-based nanomaterials for antitumor immunotherapy, showcasing the potential of novel materials in enhancing therapeutic efficacy (ref: Li doi.org/10.1002/adma.202516225/). Collectively, these studies reflect the dynamic landscape of emerging therapeutic targets in cancer and the innovative strategies being developed to improve patient outcomes.