CAR T cell therapy has emerged as a revolutionary treatment for various malignancies, particularly hematological cancers. However, the neurological effects of this therapy are a growing concern. A study by Geraghty and Acosta-Alvarez investigates the cognitive decline associated with CAR T cell therapy in animal models, revealing that acute and long-term adverse events can significantly impact patient quality of life (ref: Ward doi.org/10.1016/j.cell.2025.04.031/). Furthermore, the efficacy of CAR T cell therapy in solid tumors remains limited due to challenges such as low therapeutic efficacy and dose-limiting toxicity. Benton et al. developed mutant KRAS peptide-targeted CAR-T cells, demonstrating a potential strategy to enhance immune responses against heterogeneous tumor populations (ref: Benton doi.org/10.1016/j.ccell.2025.05.006/). Additionally, a study by Stahl identified a lymphoma-associated myeloid-monocytic gene signature that correlates with resistance to CAR T therapy, suggesting that understanding these genetic factors could improve patient outcomes (ref: Stahl doi.org/10.1016/j.ccell.2025.05.013/). The impact of aging on CAR T cell therapy response was also highlighted, with findings indicating that older patients may experience different therapeutic outcomes compared to younger cohorts (ref: Unknown doi.org/10.1038/s43018-025-00983-6/). Overall, while CAR T cell therapy shows promise, ongoing research is essential to address its limitations and optimize its application across diverse patient populations.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, particularly in lung cancer and melanoma. A phase 3 trial by Forde et al. demonstrated that neoadjuvant nivolumab combined with chemotherapy significantly improved pathological complete response and event-free survival in patients with resectable non-small-cell lung cancer (NSCLC) (ref: Forde doi.org/10.1056/NEJMoa2502931/). Similarly, Janjigian et al. reported that perioperative durvalumab led to a higher pathological complete response rate in gastric and gastroesophageal junction cancer compared to placebo, indicating the potential of ICIs in enhancing surgical outcomes (ref: Janjigian doi.org/10.1056/NEJMoa2503701/). However, the efficacy of ICIs can be influenced by genomic factors, as highlighted by Ricciuti et al., who found that DNA methyltransferase 3A mutations may predict response to PD-(L)1 blockade in NSCLC (ref: Ricciuti doi.org/10.1016/j.annonc.2025.06.003/). Additionally, Ten Ham et al. reported improved health-related quality of life in patients with metastatic melanoma treated with tumor-infiltrating lymphocytes compared to ipilimumab, emphasizing the importance of treatment modality on patient well-being (ref: Ten Ham doi.org/10.1016/j.annonc.2025.06.005/). These findings underscore the need for personalized approaches in ICI therapy to maximize efficacy and improve patient outcomes.

The tumor microenvironment (TME) plays a critical role in cancer progression and treatment resistance. Huang et al. demonstrated that bile acids activate cancer-associated fibroblasts in cholangiocarcinoma, leading to an immunosuppressive TME that promotes metastasis (ref: Huang doi.org/10.1016/j.ccell.2025.05.017/). This study highlights the need to understand the biochemical interactions within the TME to develop effective therapies. Qian et al. explored the potential of a CXCR4 partial agonist to improve immunotherapy outcomes by targeting immunosuppressive neutrophils, showing that this approach can enhance anti-PD-1 efficacy in gastric cancer models (ref: Qian doi.org/10.1016/j.ccell.2025.06.006/). Furthermore, Vitiello et al. and Rousseau et al. investigated the effects of cisplatin and temozolomide on inducing hypermutation and immune surveillance in colorectal cancer, suggesting that tailored chemotherapy can enhance immunogenicity and potentially overcome immune evasion (ref: Vitiello doi.org/10.1016/j.ccell.2025.05.014/; ref: Rousseau doi.org/10.1016/j.ccell.2025.05.010/). These studies collectively emphasize the importance of targeting the TME to improve the efficacy of cancer therapies and combat immune evasion.

Combination therapies are increasingly recognized for their potential to enhance treatment efficacy in cancer. Mountzios et al. conducted a phase 3 trial comparing tarlatamab with chemotherapy in small-cell lung cancer, finding that tarlatamab significantly improved overall survival compared to standard chemotherapy (ref: Mountzios doi.org/10.1056/NEJMoa2502099/). In the NeoCOAST-2 trial, Cascone et al. evaluated the combination of durvalumab with various agents in resectable NSCLC, reporting promising pathological complete response rates, particularly with the TROP-2 antibody-drug conjugate (ref: Cascone doi.org/10.1038/s41591-025-03746-z/). Additionally, You et al. proposed a novel nanovaccine targeting cancer stem cells and bulk tumor cells, which could address the challenge of residual disease post-surgery (ref: You doi.org/10.1038/s41565-025-01952-x/). However, Liu et al. noted that the combination of NKTR-214 with pembrolizumab did not meet primary endpoints in metastatic melanoma, highlighting the complexities and challenges of combination therapies (ref: Liu doi.org/10.1038/s43018-025-00951-0/). These findings illustrate the potential and challenges of combination therapies in improving cancer treatment outcomes.

Emerging therapies are reshaping cancer treatment paradigms, with innovative strategies focusing on enhancing immune responses and improving patient outcomes. Morath et al. introduced a PET-based tracking system for CAR T cells, enabling non-invasive monitoring of therapeutic efficacy, which could significantly enhance treatment personalization (ref: Morath doi.org/10.1038/s41551-025-01415-7/). Hunter et al. presented an in vivo CAR T cell generation strategy using targeted lipid nanoparticles, addressing the logistical challenges of CAR T cell therapy and expanding its accessibility (ref: Hunter doi.org/10.1126/science.ads8473/). Additionally, Au et al. developed multifunctional immunotherapy nanoparticles targeting clear cell renal cell carcinoma, aiming to improve treatment efficacy while reducing toxicity (ref: Au doi.org/10.1186/s12943-025-02382-y/). These advancements reflect a shift towards more personalized and effective treatment modalities, although ongoing research is necessary to validate their clinical applicability and safety.

Genomic and epigenetic factors are increasingly recognized as critical determinants of response to cancer immunotherapy. Ricciuti et al. highlighted the role of DNA methyltransferase 3A mutations in predicting the efficacy of PD-(L)1 blockade in non-small-cell lung cancer, suggesting that genomic profiling could guide treatment decisions (ref: Ricciuti doi.org/10.1016/j.annonc.2025.06.003/). The NeoCOAST-2 trial by Cascone et al. further emphasized the importance of combining neoadjuvant immunotherapy with chemotherapy and novel agents, demonstrating varying pathological complete response rates based on treatment combinations (ref: Cascone doi.org/10.1038/s41591-025-03746-z/). Additionally, You et al. proposed a nanovaccine strategy targeting cancer stem cells, integrating epigenetic regulators to enhance therapeutic efficacy (ref: You doi.org/10.1038/s41565-025-01952-x/). These studies underscore the necessity of understanding the genomic landscape of tumors to optimize immunotherapy approaches and improve patient outcomes.

Patient outcomes and quality of life are critical considerations in cancer treatment, particularly with the advent of novel immunotherapies. Ten Ham et al. reported that patients with metastatic melanoma treated with tumor-infiltrating lymphocytes experienced significantly higher health-related quality of life scores compared to those receiving ipilimumab, indicating the potential benefits of immunotherapy on patient well-being (ref: Ten Ham doi.org/10.1016/j.annonc.2025.06.005/). Additionally, Luri-Rey et al. explored the role of antigen-presenting mast cells in breast cancer immunotherapy, suggesting that enhancing these cells could improve treatment responses and patient outcomes (ref: Luri-Rey doi.org/10.1038/s41591-025-03740-5/). Wu et al. further investigated mobilizing mast cells in anti-PD-1-refractory triple-negative breast cancer, emphasizing the need for innovative strategies to overcome resistance and improve patient quality of life (ref: Wu doi.org/10.1038/s41591-025-03776-7/). These findings highlight the importance of integrating patient-reported outcomes and quality of life assessments into clinical trials to ensure comprehensive evaluation of treatment efficacy.