Recent advancements in cellular and genetic engineering have significantly enhanced the efficacy of immunotherapy. Blaeschke et al. introduced a modular pooled knockin (KI) screening platform, ModPoKI, which allows for the systematic comparison of synthetic KI sequences to optimize T cell functions, addressing the challenge of T cell dysfunction due to chronic stimulation (ref: Blaeschke doi.org/10.1016/j.cell.2023.08.013/). Cai et al. emphasized the need for comprehensive strategies to develop 'smart' CAR T cell therapies that can effectively overcome biological and practical challenges, thereby bridging the gap between the potential of adoptive cell therapy (ACT) and its clinical effectiveness (ref: Cai doi.org/10.1016/j.ccell.2023.08.011/). Furthermore, Li et al. provided a single-cell RNA sequencing atlas of CD19 CAR T cells, revealing distinct features between responders and non-responders in large B cell lymphoma, which could inform future therapeutic strategies (ref: Li doi.org/10.1016/j.ccell.2023.08.015/). Parry et al. identified ZNF683 as a marker for CD8 T cells associated with response to PD-1 blockade in Richter syndrome, highlighting the role of specific transcription factors in T cell functionality (ref: Parry doi.org/10.1016/j.ccell.2023.08.013/). In a clinical context, Houot et al. demonstrated the efficacy of axicabtagene ciloleucel as a second-line therapy for patients with relapsed or refractory large B cell lymphoma, supporting its use in patients ineligible for autologous stem cell transplantation (ref: Houot doi.org/10.1038/s41591-023-02572-5/). Gong et al. explored in situ PEGylation of CAR T cells, which mitigated cytokine release syndrome and neurotoxicity, thus enhancing the safety profile of CAR T therapies (ref: Gong doi.org/10.1038/s41563-023-01646-6/). Additionally, Derrien et al. uncovered mechanisms of acquired resistance to GPRC5D-targeted therapies in multiple myeloma, emphasizing the importance of genetic and epigenetic profiling in guiding immunotherapy choices (ref: Derrien doi.org/10.1038/s43018-023-00625-9/). Lin et al. innovatively combined engineered bacteria with iridium(III) photosensitizers to improve photodynamic therapy targeting solid tumors, showcasing the potential of hybrid approaches in cancer treatment (ref: Lin doi.org/10.1002/anie.202310158/).

The exploration of immune checkpoint inhibition has revealed both promising therapeutic avenues and significant resistance mechanisms. Chen et al. conducted a phase 2 study on the efficacy of atezolizumab in advanced alveolar soft part sarcoma, highlighting the potential of immune checkpoint inhibitors in rare cancers (ref: Chen doi.org/10.1056/NEJMoa2303383/). Wang et al. demonstrated that targeting tumor-associated bacteria with a liposomal antibiotic can generate neoantigens, leading to enhanced anti-tumor immune responses and improved disease-free survival in colorectal cancer patients (ref: Wang doi.org/10.1038/s41587-023-01957-8/). Ferrari et al. found that microbiota-derived metabolites can upregulate HLA class I expression on cancer cells, sensitizing them to immune checkpoint inhibitors, thereby addressing a common evasion mechanism (ref: Ferrari doi.org/10.1016/j.ccell.2023.08.014/). In the context of non-small-cell lung cancer, Besse et al. evaluated the cancer vaccine OSE2101 against chemotherapy, revealing its potential to overcome resistance in patients previously treated with immune checkpoint blockers (ref: Besse doi.org/10.1016/j.annonc.2023.07.006/). Lee et al. investigated antigen escape mechanisms in multiple myeloma, identifying downregulation of BCMA and GPRC5D as critical factors in resistance to targeted therapies (ref: Lee doi.org/10.1038/s41591-023-02491-5/). Westcott et al. highlighted that mismatch repair deficiency alone does not guarantee tumor immunogenicity, suggesting that additional factors influence the response to immune checkpoint blockade (ref: Westcott doi.org/10.1038/s41588-023-01499-4/). Taraborrelli et al. found that high expression of the autophagy gene ATG16L1 in colorectal cancer correlates with poor responses to anti-PD-L1 therapy, indicating tumor-intrinsic factors that contribute to immunotherapy resistance (ref: Taraborrelli doi.org/10.1038/s41467-023-41618-7/).

The tumor microenvironment (TME) plays a crucial role in shaping immune responses and therapeutic outcomes. Li et al. provided insights into the immune landscape of CD19 CAR T cells in large B cell lymphoma, revealing distinct cellular features that correlate with treatment responses, which could inform future therapeutic strategies (ref: Li doi.org/10.1016/j.ccell.2023.08.015/). Yang et al. identified genetic variants in microglia that contribute to Alzheimer's disease, emphasizing the importance of understanding immune cell interactions in the brain (ref: Yang doi.org/10.1038/s41588-023-01506-8/). van de Donk et al. reported on the efficacy of carfilzomib and lenalidomide in treating primary plasma cell leukemia, highlighting the need for effective therapies in hematologic malignancies (ref: van de Donk doi.org/10.1016/S1470-2045(23)00405-9/). Pan et al. investigated the dynamic immune evasion mechanisms in pancreatic cancer, identifying the role of cancer-associated fibroblasts in promoting T-cell exhaustion (ref: Pan doi.org/10.1002/adma.202305798/). Liu et al. developed nanoparticles that enhance STING signaling in the TME, promoting a more favorable immune response by reducing regulatory T cells and polarizing macrophages towards an M1 phenotype (ref: Liu doi.org/10.1002/adma.202304845/). Rodriguez et al. characterized a macrocyclic peptide that effectively blocks PD-L1, providing a potential alternative to traditional monoclonal antibodies in immunotherapy (ref: Rodriguez doi.org/10.1186/s12943-023-01853-4/). Li et al. also explored the immune microenvironment in NASH-associated hepatocellular carcinoma, revealing critical interactions that underlie immunosuppression and potential therapeutic targets (ref: Li doi.org/10.1097/HEP.0000000000000591/). Lastly, the use of camel nanobodies in CAR T cell therapy demonstrated high efficacy against solid tumors, showcasing innovative strategies to enhance immune responses (ref: Li doi.org/10.1038/s41467-023-41631-w/).

Innovative therapeutic strategies are emerging to enhance the efficacy of existing cancer treatments. Houot et al. evaluated axicabtagene ciloleucel as a second-line therapy in patients with relapsed or refractory large B cell lymphoma, demonstrating its potential in those ineligible for autologous stem cell transplantation (ref: Houot doi.org/10.1038/s41591-023-02572-5/). Umemura et al. conducted a phase 1 trial combining two adenoviral vectors for high-grade glioma, showing safety and feasibility, which warrants further investigation (ref: Umemura doi.org/10.1016/S1470-2045(23)00347-9/). Leal et al. compared tumor treating fields therapy combined with standard systemic therapy against standard therapy alone in metastatic non-small-cell lung cancer, revealing important safety data and efficacy outcomes (ref: Leal doi.org/10.1016/S1470-2045(23)00344-3/). An et al. introduced a novel approach by attaching bacteria to macrophages to enhance their efficacy against solid tumors, leveraging the immunogenic properties of bacteria (ref: An doi.org/10.1002/adma.202305384/). Wang et al. developed a bioinspired nanozyme that disrupts reactive oxygen species homeostasis, enhancing immunotherapy responses in cold tumors (ref: Wang doi.org/10.1002/adma.202306748/). Sridhar et al. analyzed the impact of avelumab maintenance therapy in advanced urothelial carcinoma, demonstrating improved survival outcomes in patients who started treatment after a defined interval post-chemotherapy (ref: Sridhar doi.org/10.1016/j.eururo.2023.08.001/). Green et al. investigated the role of immunosuppressive Tregs in liver metastases, providing insights into resistance mechanisms to immune checkpoint inhibitors (ref: Green doi.org/10.1136/gutjnl-2023-330024/).

Clinical trials continue to provide critical insights into the efficacy of immunotherapies across various cancer types. Besse et al. conducted a randomized controlled study comparing the cancer vaccine OSE2101 to chemotherapy in advanced non-small-cell lung cancer, revealing its potential to overcome resistance to immune checkpoint blockers (ref: Besse doi.org/10.1016/j.annonc.2023.07.006/). Miao et al. explored the role of CMTM6 in modulating T cell responses, highlighting its importance in regulating immune checkpoint expression and antitumor immunity (ref: Miao doi.org/10.1016/j.ccell.2023.08.008/). Umemura et al. reported on the safety and activity of combined cytotoxic and immune-stimulatory gene therapy for high-grade glioma, indicating a promising avenue for future research (ref: Umemura doi.org/10.1016/S1470-2045(23)00347-9/). van de Donk et al. provided final analysis results from a phase 2 study on primary plasma cell leukemia, demonstrating improved outcomes with carfilzomib and lenalidomide (ref: van de Donk doi.org/10.1016/S1470-2045(23)00405-9/). Marone et al. investigated the efficacy of epitope-engineered hematopoietic stem cells in evading CD123-targeted immunotherapy, emphasizing the need for innovative strategies in myeloid malignancies (ref: Marone doi.org/10.1084/jem.20231235/). Li et al. demonstrated the effectiveness of camel nanobody-based CAR-T cells against large solid tumors, showcasing the potential of novel antibody formats in immunotherapy (ref: Li doi.org/10.1038/s41467-023-41631-w/). Noviello et al. reported on the long-term follow-up of guadecitabine combined with ipilimumab in unresectable melanoma, highlighting the promise of hypomethylating agents in enhancing immune checkpoint inhibitor efficacy (ref: Noviello doi.org/10.1038/s41467-023-40994-4/).

Metabolic pathways play a crucial role in shaping immune responses and therapeutic efficacy in cancer. Miller et al. explored the role of acetate metabolism in bolstering T-cell effector function, proposing that targeting acetyl-CoA synthetase 2 (ACSS2) could enhance antitumor immunity (ref: Miller doi.org/10.1038/s43018-023-00636-6/). Miao et al. highlighted the significance of CMTM6 in regulating the expression of immune checkpoint molecules, which can influence T cell responses and tumor evasion (ref: Miao doi.org/10.1016/j.ccell.2023.08.008/). Goswami et al. demonstrated that inhibiting KDM6B in myeloid cells can sensitize glioblastoma to PD-1 blockade, suggesting that epigenetic regulation of immune cells can enhance immunotherapy outcomes (ref: Goswami doi.org/10.1038/s43018-023-00620-0/). Rowe et al. found that formate supplementation can enhance CD8+ T-cell fitness and improve the efficacy of PD-1 blockade in tumor models, indicating the importance of metabolic support in immunotherapy (ref: Rowe doi.org/10.1158/2159-8290.CD-22-1301/). Yang et al. identified genetic variants in microglia associated with Alzheimer's disease, emphasizing the relevance of metabolic pathways in immune modulation beyond cancer (ref: Yang doi.org/10.1038/s41588-023-01506-8/). Bobisse et al. reported on a phase 1 trial of vaccine-primed T cell transfer in ovarian cancer, highlighting the potential of metabolic reprogramming in enhancing immune responses (ref: Bobisse doi.org/10.1038/s43018-023-00623-x/). Deng et al. introduced SCAR, a resource for single-cell and spatially-resolved cancer research, which can facilitate the understanding of metabolic features in the tumor microenvironment (ref: Deng doi.org/10.1093/nar/).

Tumor immunology and the mechanisms of antigen presentation are critical for the development of effective immunotherapies. Cai et al. discussed the challenges in implementing CAR T cell therapies, emphasizing the need for innovative strategies to enhance their effectiveness (ref: Cai doi.org/10.1016/j.ccell.2023.08.011/). Blaeschke et al. introduced a modular approach for synthetic knockin sequences to improve T cell functions, which could enhance the durability of cell therapies (ref: Blaeschke doi.org/10.1016/j.cell.2023.08.013/). Wang et al. demonstrated that targeting tumor-associated bacteria can generate neoantigens, leading to enhanced immune responses and improved patient outcomes in colorectal cancer (ref: Wang doi.org/10.1038/s41587-023-01957-8/). Chen et al. reported on the efficacy of atezolizumab in advanced alveolar soft part sarcoma, highlighting the potential of immune checkpoint inhibitors in rare tumors (ref: Chen doi.org/10.1056/NEJMoa2303383/). Rodriguez et al. characterized a macrocyclic peptide that effectively blocks PD-L1, providing an alternative to traditional monoclonal antibodies in immunotherapy (ref: Rodriguez doi.org/10.1186/s12943-023-01853-4/). Li et al. demonstrated the effectiveness of camel nanobody-based CAR-T cells against solid tumors, showcasing innovative approaches to enhance immune responses (ref: Li doi.org/10.1038/s41467-023-41631-w/). Lastly, Noviello et al. explored the combination of guadecitabine with ipilimumab in melanoma, indicating the potential of hypomethylating agents to enhance immune checkpoint inhibitor efficacy (ref: Noviello doi.org/10.1038/s41467-023-40994-4/).