Recent advancements in gene editing technologies have significantly enhanced the potential of immunotherapy, particularly through the use of adeno-associated viruses (AAV) for genetic engineering of T cells. Nyberg et al. demonstrated that an evolved AAV variant can efficiently target large transgenes to murine T cells via homology-directed repair, which is crucial for improving adoptive cell therapies and understanding T cell biology (ref: Nyberg doi.org/10.1016/j.cell.2022.12.022/). In a complementary study, Dai et al. introduced CLASH, a high-throughput system that utilizes Cas12a/Cpf1 mRNA and pooled AAVs for simultaneous gene editing and transgene knock-in, achieving unprecedented efficiency in human T cell engineering (ref: Dai doi.org/10.1038/s41587-022-01639-x/). These methodologies not only enhance the precision of genetic modifications but also open new avenues for experimental T cell immunology, emphasizing the need for efficient gene targeting in murine models to translate findings into human applications. Moreover, the role of tumor mutation burden (TMB) in immunotherapy response has been scrutinized, with Niknafs et al. revealing that persistent mutation burden can drive sustained anti-tumor immune responses across various cancer types (ref: Niknafs doi.org/10.1038/s41591-022-02163-w/). This finding highlights the complexity of immune responses and the necessity for further exploration into how genetic alterations influence therapeutic outcomes. Additionally, Schiepers et al. explored the dynamics of serum antibody responses to repeated immunizations, shedding light on the mechanisms of original antigenic sin and its implications for vaccine design (ref: Schiepers doi.org/10.1038/s41586-023-05715-3/). Together, these studies underscore the intricate interplay between genetic engineering, immune response modulation, and therapeutic efficacy in cancer treatment.

Checkpoint inhibition has emerged as a cornerstone of cancer immunotherapy, yet resistance mechanisms continue to challenge its efficacy. Qiu et al. investigated how cancer cells develop interferon-associated epigenetic memory, which contributes to T cell dysfunction and resistance to immune checkpoint blockade (ref: Qiu doi.org/10.1038/s43018-022-00490-y/). This study highlights the need for understanding the molecular underpinnings of immune evasion to enhance therapeutic strategies. In a related context, Suzuki et al. identified that certain anti-PD-1 antibodies can act as PD-1 agonists, potentially down-regulating inflammatory diseases, thus presenting a dual role for these antibodies in both enhancing and modulating immune responses (ref: Suzuki doi.org/10.1126/sciimmunol.add4947/). Furthermore, Jneid et al. focused on the role of STING stimulation in dendritic cells, demonstrating its importance in priming antitumor T cell responses, particularly in nonimmunogenic tumors (ref: Jneid doi.org/10.1126/sciimmunol.abn6612/). This underscores the potential of STING as a therapeutic target to enhance immune responses. The RET-MAP study by Aldea et al. provided insights into the clinicobiologic features of lung cancer patients with RET fusions, revealing low tumor mutational burden and PD-L1 expression, which may influence responses to checkpoint inhibitors (ref: Aldea doi.org/10.1016/j.jtho.2022.12.018/). Collectively, these findings emphasize the complexity of immune modulation in cancer therapy and the necessity for tailored approaches to overcome resistance.

The tumor microenvironment plays a critical role in shaping immune responses and influencing the efficacy of immunotherapies. Mailankody et al. presented interim results from the UNIVERSAL trial, evaluating allogeneic BCMA-targeting CAR T cells in multiple myeloma, highlighting the safety and tolerability of this innovative approach (ref: Mailankody doi.org/10.1038/s41591-022-02182-7/). This study emphasizes the potential of engineered T cells to overcome the challenges posed by the tumor microenvironment, particularly in hematological malignancies. In parallel, Lester et al. explored the impact of dietary fucosylation on melanoma cells, demonstrating that it enhances the expression of HLA-DRB1, thereby improving CD4 T cell responses (ref: Lester doi.org/10.1038/s43018-022-00506-7/). Additionally, Hong et al. investigated the efficacy of autologous T cell therapy targeting MAGE-A4 in various solid tumors, revealing promising results in enhancing anti-tumor immunity (ref: Hong doi.org/10.1038/s41591-022-02128-z/). The interplay between epigenetic modifications and immune evasion was further elucidated by Lin et al., who found that YTHDF1 promotes MHC-I degradation, facilitating immune escape (ref: Lin doi.org/10.1038/s41467-022-35710-7/). These studies collectively highlight the multifaceted interactions within the tumor microenvironment that dictate immune responses, underscoring the need for innovative strategies to enhance therapeutic efficacy.

Innovative therapeutic strategies are crucial for improving outcomes in cancer treatment, particularly through the combination of existing therapies with novel agents. Yap et al. conducted phase I trials on IACS-010759, a complex I inhibitor targeting oxidative phosphorylation, in patients with advanced solid tumors and acute myeloid leukemia, aiming to establish safety and tolerability (ref: Yap doi.org/10.1038/s41591-022-02103-8/). Despite the challenges associated with targeting metabolic pathways, these trials represent a significant step toward integrating metabolic inhibitors into cancer therapy. Complementing this, Ma et al. developed a composite hydrogel for spatiotemporal lipid intervention, demonstrating its potential to enhance immunogenic cell death (ICD) in cancer cells (ref: Ma doi.org/10.1002/adma.202211579/). Moreover, Horton et al. explored the combination of an IL-2 variant fused to an anti-PD-1 antibody, which showed promise in overcoming systemic toxicities associated with IL-2 therapy while promoting tumor control (ref: Horton doi.org/10.1016/j.immuni.2022.12.012/). This innovative approach highlights the potential of combining immune modulators to enhance therapeutic efficacy. Similarly, Tichet et al. evaluated a bispecific PD1-IL2v and anti-PD-L1 strategy, demonstrating its ability to break tumor immunity resistance by enhancing CD8 T cell responses (ref: Tichet doi.org/10.1016/j.immuni.2022.12.006/). These studies underscore the importance of innovative combination strategies in overcoming resistance mechanisms and improving patient outcomes in cancer therapy.

Cancer vaccines and antibody engineering are at the forefront of immunotherapeutic strategies, aiming to enhance anti-tumor responses. Liu et al. investigated GD2-specific fourth-generation safety-designed CAR T cells in glioblastoma, demonstrating their safety and potential anti-tumor activity, despite challenges such as antigen loss in tumors (ref: Liu doi.org/10.1186/s12943-022-01711-9/). This study highlights the need for continuous innovation in CAR T cell design to maintain efficacy against evolving tumor antigens. In a complementary approach, Li et al. developed tumor cell nanovaccines based on genetically engineered antibody-anchored membranes, which showed enhanced antitumor efficacy in both immunogenic and non-immunogenic tumor models (ref: Li doi.org/10.1002/adma.202208923/). These advancements in vaccine design emphasize the importance of incorporating costimulatory signals to boost immune responses. The integration of engineered antibodies into vaccine platforms represents a promising direction for enhancing the efficacy of cancer immunotherapy. Together, these studies underscore the potential of innovative vaccine strategies and antibody engineering in eliciting robust immune responses against tumors, paving the way for more effective cancer treatments.

Clinical trials and real-world evidence play a pivotal role in assessing the effectiveness of cancer therapies, particularly in the context of immunotherapy. Hong et al. conducted a multicenter, dose-escalation phase 1 trial of afamitresgene autoleucel, an autologous T cell therapy targeting MAGE-A4, in patients with various solid tumors, demonstrating its potential in enhancing anti-tumor responses (ref: Hong doi.org/10.1038/s41591-022-02128-z/). This study highlights the importance of rigorous clinical evaluation in translating novel therapies into clinical practice. Additionally, Vikas et al. endorsed guidelines for mismatch repair and microsatellite instability testing for immune checkpoint inhibitor therapy, emphasizing the need for standardized testing to optimize patient selection (ref: Vikas doi.org/10.1200/JCO.22.02462/). Shah et al. provided insights into the use of immunotherapy and targeted therapy for advanced gastroesophageal cancer, recommending specific treatment regimens based on PD-L1 expression levels (ref: Shah doi.org/10.1200/JCO.22.02331/). Furthermore, Carroll et al. assessed the adoption of immunotherapies across oncology practices, revealing significant variations in adoption rates, which may impact patient access to novel treatments (ref: Carroll doi.org/10.1001/jamaoncol.2022.6296/). These studies collectively underscore the critical role of clinical trials and real-world evidence in shaping treatment paradigms and ensuring that innovative therapies reach patients effectively.

Tumor immunology and the identification of biomarkers are essential for understanding cancer progression and treatment responses. Gounder et al. conducted a phase I study of milademetan, an MDM2 inhibitor, in patients with advanced liposarcoma and other solid tumors, reporting a disease control rate of 45.8% and a median progression-free survival of 4.0 months (ref: Gounder doi.org/10.1200/JCO.22.01285/). This study highlights the potential of targeting specific molecular pathways to improve patient outcomes. In a related study, Zhou et al. extended the follow-up of the CameL phase 3 trial, demonstrating that the addition of camrelizumab to chemotherapy significantly improved overall survival in patients with advanced nonsquamous NSCLC (ref: Zhou doi.org/10.1016/j.jtho.2022.12.017/). Moreover, Aldea et al. provided insights into the clinicobiologic features of lung cancer patients harboring RET fusions, revealing low tumor mutational burden and PD-L1 expression, which may influence treatment responses (ref: Aldea doi.org/10.1016/j.jtho.2022.12.018/). These findings underscore the importance of biomarker identification in tailoring immunotherapy approaches and enhancing therapeutic efficacy. Together, these studies illustrate the dynamic interplay between tumor immunology and biomarker discovery, paving the way for more personalized cancer treatment strategies.

The exploration of metabolic pathways in cancer therapy has gained traction, revealing new therapeutic targets and strategies. Tao et al. identified the role of the capsaicin receptor TRPV1 in maintaining quiescence of hepatic stellate cells, suggesting its potential as a therapeutic target in liver fibrosis (ref: Tao doi.org/10.1016/j.jhep.2022.12.031/). This study highlights the importance of understanding metabolic regulation in tumor-associated cells and its implications for cancer therapy. In a related study, Li et al. demonstrated that nicotinamide N-methyltransferase (NNMT) promotes M2 macrophage polarization and myeloid-derived suppressor cell conversion in gallbladder carcinoma, indicating its role in shaping the tumor immune microenvironment (ref: Li doi.org/10.1097/HEP.0000000000000028/). Furthermore, Zhang et al. developed engineered exosomes for the in situ reprogramming of tumor-associated macrophages, showcasing a novel approach to enhance immunotherapy efficacy (ref: Zhang doi.org/10.1002/anie.202217089/). Lin et al. elucidated the role of YTHDF1 in promoting immune evasion through MHC-I degradation, emphasizing the impact of RNA methylation on tumor immunity (ref: Lin doi.org/10.1038/s41467-022-35710-7/). These studies collectively underscore the significance of metabolic pathways in cancer therapy and the potential for innovative strategies to enhance therapeutic responses.