Recent advancements in immunotherapy have focused on enhancing the efficacy and specificity of treatments through innovative mechanisms. A study by Zhou et al. introduced a novel approach using bispecific antibodies and chimeric antigen receptor (CAR) T cells that target tumor-associated carbohydrate antigens with a density-dependent mechanism, aiming to minimize off-target toxicity while maximizing therapeutic effects (ref: Zhou doi.org/10.1016/j.cell.2025.09.001/). In a phase 2 trial, Rouce et al. demonstrated that tisagenlecleucel, a CAR T-cell therapy, achieved durable remissions in pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia, highlighting the potential of CAR T-cell therapies despite transient high-grade toxicities (ref: Rouce doi.org/10.1038/s41577-025-01228-4/). Furthermore, Park et al. explored a photoresponsive nanoproteolysis-targeting chimera (Nano-PROTAC) that reprograms cancer metabolism to enhance pyroptosis-mediated immunotherapy, addressing the metabolic barriers that limit the efficacy of photodynamic therapy (ref: Park doi.org/10.1038/s41392-025-02405-6/). The tumor microenvironment (TME) plays a critical role in shaping the response to immunotherapy. Xiao et al. utilized single-cell RNA sequencing to uncover metabolic interactions between tumors and macrophages in triple-negative breast cancer, revealing that heme binding protein 2 (HEBP2) governs glutamine competition, which significantly impacts immunotherapy efficacy (ref: Xiao doi.org/10.1016/j.cmet.2025.08.009/). Additionally, the ESMO-ESTRO consensus statements emphasized the need for evidence-based guidelines on the safety of combining radiotherapy with immune checkpoint inhibitors, acknowledging the potential for improved outcomes alongside increased toxicity (ref: van Aken doi.org/10.1016/j.annonc.2025.09.008/). Storey et al. introduced a targeted radio-immunotheranostic approach using a monoclonal antibody against LRRC15, which could deplete pro-tumorigenic mechanisms and enhance immunotherapy resistance (ref: Storey doi.org/10.1038/s41392-025-02410-9/). Overall, these studies underscore the multifaceted strategies being developed to enhance immunotherapy efficacy while addressing the challenges posed by the TME.

Combination therapies have emerged as a promising strategy to enhance treatment efficacy and overcome resistance in various cancers. Li et al. characterized the microenvironment of large B cell lymphomas (LBCL) using single-nucleus multiome profiling, identifying distinct archetype profiles that correlate with treatment responses, particularly noting the roles of cancer-associated fibroblasts and tumor-associated macrophages (ref: Li doi.org/10.1016/j.ccell.2025.06.002/). In a phase 2 trial, Reuss et al. investigated the efficacy of neoadjuvant nivolumab and nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma, revealing the potential of immune checkpoint blockade in the perioperative setting (ref: Reuss doi.org/10.1038/s41591-025-03958-3/). Gimeno-Valiente et al. explored the interplay between DNA methylation and genomic alterations in non-small cell lung cancer (NSCLC), providing insights into tumor evolution and potential biomarkers for treatment response (ref: Gimeno-Valiente doi.org/10.1038/s41588-025-02307-x/). Jiao et al. demonstrated that combining transarterial chemoembolization (TACE) with PD-(L)1 inhibitors significantly reduced resistance and improved survival in advanced hepatocellular carcinoma, suggesting a new standard treatment approach (ref: Jiao doi.org/10.5306/wjco.v16.i8.109419/). Liu et al. reported on the survival benefits of concurrent immune checkpoint inhibitors and radiotherapy in NSCLC patients with brain metastases, emphasizing the importance of combination strategies in improving patient outcomes (ref: Liu doi.org/10.5306/wjco.v16.i8.107009/). Overall, these studies highlight the critical role of combination therapies in enhancing treatment efficacy and addressing resistance mechanisms across various cancer types.

The tumor microenvironment (TME) is a crucial factor influencing immune evasion and therapeutic efficacy in cancer treatment. Xiao et al. investigated the metabolic interactions between tumors and macrophages in triple-negative breast cancer, revealing that HEBP2 governs glutamine competition, which significantly affects the efficacy of immunotherapy (ref: Xiao doi.org/10.1016/j.cmet.2025.08.009/). Han et al. proposed a novel strategy to prevent glioblastoma relapse by inducing mitochondrial stress in the surgical cavity, thereby enhancing innate immune activation and potentially improving adaptive immunity against tumor recurrence (ref: Han doi.org/10.1002/adma.202511351/). Gimeno-Valiente et al. further elucidated the role of DNA methylation in NSCLC evolution, highlighting how aberrant methylation patterns can contribute to immune evasion and treatment resistance (ref: Gimeno-Valiente doi.org/10.1038/s41588-025-02307-x/). Rouce et al. provided evidence for the durable efficacy of CAR T-cell therapy in pediatric patients with relapsed B-cell ALL, emphasizing the importance of overcoming the immunosuppressive TME for successful treatment outcomes (ref: Rouce doi.org/10.1038/s41577-025-01228-4/). Additionally, Chen et al. identified UGCG as a metabolic checkpoint that governs immune activation and tumor immune evasion, suggesting potential therapeutic targets to enhance immunotherapy effectiveness (ref: Chen doi.org/10.1038/s41392-025-02413-6/). Collectively, these studies underscore the intricate relationship between the TME and immune responses, highlighting the need for targeted strategies to enhance immunotherapy efficacy.

Targeted therapies and biomarkers are pivotal in personalizing cancer treatment and improving patient outcomes. Gimeno-Valiente et al. conducted a comprehensive analysis of DNA methylation and genomic alterations in NSCLC, revealing critical insights into tumor evolution and potential biomarkers for treatment response (ref: Gimeno-Valiente doi.org/10.1038/s41588-025-02307-x/). The ESMO-ESTRO consensus statements addressed the safety of combining radiotherapy with immune checkpoint inhibitors, VEGF inhibitors, and multitargeted tyrosine kinase inhibitors, emphasizing the need for evidence-based guidelines in clinical practice (ref: van Aken doi.org/10.1016/j.annonc.2025.09.008/). Reuss et al. explored the role of circulating tumor DNA (ctDNA) in assessing the efficacy of neoadjuvant nivolumab and nivolumab/ipilimumab in resectable diffuse pleural mesothelioma, highlighting ctDNA as a promising biomarker for monitoring treatment response (ref: Reuss doi.org/10.1038/s41591-025-03958-3/). Park et al. introduced a photoresponsive nanoproteolysis-targeting chimera (Nano-PROTAC) that enhances pyroptosis-mediated immunotherapy by reprogramming cancer metabolism, showcasing the potential of targeted metabolic interventions (ref: Park doi.org/10.1038/s41392-025-02405-6/). Long et al. reported on the efficacy of neoadjuvant PD-1 and LAG-3-targeting bispecific antibodies in melanoma, providing insights into the potential of combining immune checkpoint inhibitors for improved pathological response rates (ref: Long doi.org/10.1038/s41591-025-03967-2/). These studies collectively underscore the importance of targeted therapies and biomarkers in advancing personalized cancer treatment.

Clinical trials play a crucial role in evaluating the efficacy and safety of novel cancer therapies, with recent studies highlighting significant findings in various cancer types. Qiu et al. conducted a randomized clinical trial comparing consolidative nivolumab versus observation in unresectable stage III NSCLC patients following neoadjuvant therapy, demonstrating that nivolumab consolidation significantly improved progression-free survival (PFS) compared to observation (ref: Qiu doi.org/10.1038/s41392-025-02408-3/). Canavan et al. examined the association between systemic anticancer therapy administration near the end of life and healthcare utilization, revealing that all subtypes of systemic anticancer therapy were linked to adverse quality of life and lower hospice utilization (ref: Canavan doi.org/10.1200/JCO-25-00530/). Cotait Maluf et al. reported on the HERCULES clinical trial, which demonstrated the efficacy of pembrolizumab combined with platinum-based chemotherapy in advanced penile cancer, providing a manageable safety profile despite high rates of treatment-related adverse events (ref: Cotait Maluf doi.org/10.1001/jamaoncol.2025.3266/). Bruno et al. identified nuclear respiratory factor 1 as a master regulator of survival pathways in multiple myeloma under proteasome inhibition therapy, highlighting the need for targeted approaches in this challenging malignancy (ref: Bruno doi.org/10.1182/blood.2025028441/). Additionally, Xiang et al. investigated the mechanisms underlying the efficacy of chemoimmunotherapy in esophageal squamous cell carcinoma, emphasizing the need to decipher resistance factors to improve patient outcomes (ref: Xiang doi.org/10.1136/gutjnl-2025-335642/). These findings collectively underscore the importance of clinical trials in shaping cancer treatment strategies and improving patient outcomes.

Understanding the cellular and molecular mechanisms underlying cancer progression and treatment response is essential for developing effective therapies. Gimeno-Valiente et al. explored the interplay between DNA methylation and genomic alterations in non-small cell lung cancer (NSCLC), revealing how these factors cooperate during tumor evolution and providing insights into potential biomarkers for treatment response (ref: Gimeno-Valiente doi.org/10.1038/s41588-025-02307-x/). Li et al. characterized the microenvironment of large B cell lymphomas (LBCL) using single-nucleus multiome profiling, identifying distinct cellular archetypes that correlate with treatment responses, particularly noting the roles of cancer-associated fibroblasts and tumor-associated macrophages (ref: Li doi.org/10.1016/j.ccell.2025.06.002/). Park et al. introduced a photoresponsive nanoproteolysis-targeting chimera (Nano-PROTAC) that enhances pyroptosis-mediated immunotherapy by reprogramming cancer metabolism, addressing the metabolic barriers that limit the efficacy of photodynamic therapy (ref: Park doi.org/10.1038/s41392-025-02405-6/). Rouce et al. provided evidence for the durable efficacy of CAR T-cell therapy in pediatric patients with relapsed B-cell ALL, emphasizing the importance of overcoming the immunosuppressive tumor microenvironment for successful treatment outcomes (ref: Rouce doi.org/10.1038/s41577-025-01228-4/). Furthermore, Natesh et al. discussed advances and challenges in developing human 3D solid tumor models, which are crucial for elucidating drivers of oncogenesis and therapeutic responses (ref: Natesh doi.org/10.1002/adfm.202419912/). Collectively, these studies highlight the intricate cellular and molecular mechanisms that govern cancer biology and treatment responses.

Emerging technologies are revolutionizing cancer immunotherapy by enhancing precision and efficacy. Ciancaglini et al. demonstrated that macrophages regulate PD-1 and CTLA-4 expression on type 2 innate lymphoid cells (ILC2s) within the tumor microenvironment, revealing new insights into lymphocyte dysfunction and potential therapeutic targets (ref: Ciancaglini doi.org/10.1038/s41423-025-01347-x/). Scheid et al. introduced MHCquant2, a scalable pipeline for immunopeptidomics that refines tumor antigen discovery, facilitating high-throughput analyses and advancing cancer immunotherapy (ref: Scheid doi.org/10.1186/s13059-025-03763-8/). Natesh et al. reviewed the advances and challenges in developing human 3D solid tumor models, which are essential for understanding tumor biology and therapeutic responses (ref: Natesh doi.org/10.1002/adfm.202419912/). Chun et al. reported on the design of a potent interleukin-21 mimic for cancer immunotherapy, highlighting the potential of computational protein design to tailor therapeutic proteins for enhanced efficacy (ref: Chun doi.org/10.1126/sciimmunol.adx1582/). Sinha et al. identified the RNA-binding protein GCN1 as a key player in hepatic metastasis, suggesting that targeting metabolic pathways may enhance immunotherapy effectiveness (ref: Sinha doi.org/10.1158/2159-8290.CD-24-1055/). Jia et al. engineered a dual-locked immuno-polymeric nanoplatform for spatiotemporal control over STING agonists, enhancing cancer immunotherapy precision (ref: Jia doi.org/10.1002/anie.202514516/). These studies collectively underscore the transformative potential of emerging technologies in advancing cancer immunotherapy.