Recent studies have elucidated various mechanisms underlying immune checkpoint inhibition, particularly focusing on LAG3 and PD-L1 pathways. Jiang et al. demonstrated that ligand-induced non-K48-linked polyubiquitination of LAG3 enhances its inhibitory function by preventing the sequestration of signaling motifs, thus promoting immune suppression in the tumor microenvironment (ref: Jiang doi.org/10.1016/j.cell.2025.02.014/). In a clinical context, Chen et al. found that low-dose irradiation of the gut significantly improves the efficacy of PD-L1 blockade in metastatic cancer patients, suggesting that the gut microbiota and immune interactions play a crucial role in enhancing the therapeutic effects of immune checkpoint inhibitors (ref: Chen doi.org/10.1016/j.ccell.2025.02.010/). Furthermore, studies by Desaunay et al. and Lubrano et al. identified resistance mechanisms in melanoma therapies, highlighting the RhoA-FAK-AKT signaling pathway as a critical target for overcoming resistance to both targeted therapies and immune checkpoint inhibitors (ref: Desaunay doi.org/10.1016/j.ccell.2025.02.012/; Lubrano doi.org/10.1016/j.ccell.2025.02.001/). Li et al. also contributed to this theme by comparing various neoadjuvant therapies in head and neck squamous cell carcinoma, revealing that combination therapies yield higher pathologic response rates and improved survival outcomes compared to monotherapies (ref: Li doi.org/10.1016/j.ccell.2025.02.026/).

Innovations in CAR T-cell therapy have focused on enhancing the efficacy and persistence of these engineered cells in treating various malignancies. Pham-Danis et al. highlighted the limitations of second-generation CAR T-cells in targeting antigen-low cells, proposing that restoring LAT activity can significantly improve sensitivity and persistence in acute lymphoblastic leukemia (ref: Pham-Danis doi.org/10.1016/j.ccell.2025.02.008/). Wang et al. introduced the ALA-CART platform, which enhances CAR T-cell functionality by improving LAT phosphorylation, thereby increasing cytotoxic responses against antigen-low tumors (ref: Wang doi.org/10.1016/j.ccell.2025.02.021/). In the context of triple-negative breast cancer, Liu et al. utilized single-cell RNA sequencing to reveal distinct immune cell dynamics in response to chemoimmunotherapy, emphasizing the role of mast cells in mediating immune activation (ref: Liu doi.org/10.1016/j.ccell.2025.02.016/). Ikeda et al. explored CAR T-cells targeting mismatched HLA-DR molecules in acute myeloid leukemia, identifying KG2032 as a promising monoclonal antibody that selectively binds to leukemia cells, thus enhancing therapeutic specificity (ref: Ikeda doi.org/10.1038/s43018-025-00934-1/). Lastly, Yang et al. investigated the impact of CREBBP mutations on enhancer activation in lymphomas, suggesting that enforced CD4 T-cell engagement could restore functionality in these cases (ref: Yang doi.org/10.1182/blood.2024026664/).

The tumor microenvironment (TME) plays a pivotal role in shaping immune responses and facilitating immune evasion. Chang et al. explored bacterial immunotherapy, revealing that engineered Salmonella enterica can evade immune defenses while simultaneously stimulating anti-tumor responses, highlighting a dual mechanism that could enhance therapeutic efficacy (ref: Chang doi.org/10.1016/j.cell.2025.02.002/). Liu et al. conducted a comprehensive single-cell analysis of non-small cell lung cancer (NSCLC) patients treated with anti-PD-1 therapy, uncovering significant immune heterogeneity that correlates with variable treatment responses, thus emphasizing the need for personalized approaches in immunotherapy (ref: Liu doi.org/10.1016/j.cell.2025.03.018/). In a clinical trial, Xu et al. demonstrated that combining nivolumab with induction chemotherapy and radiotherapy in nasopharyngeal carcinoma resulted in impressive survival rates, with a 3-year overall survival of 97.9%, underscoring the potential of integrating immunotherapy with traditional modalities (ref: Xu doi.org/10.1016/j.ccell.2025.01.014/). Additionally, Ma et al. investigated the genetic and epigenetic mechanisms of GPRC5D loss in multiple myeloma post-CAR T-cell therapy, providing insights into resistance mechanisms that could inform future therapeutic strategies (ref: Ma doi.org/10.1182/blood.2024026622/).

Bacterial and viral immunotherapy approaches are gaining traction as promising strategies in cancer treatment. Jiang et al. examined the role of HIF in regulating endogenous retroviruses in clear cell renal cell carcinoma (ccRCC), suggesting that HIF-responsive ERVs may serve as potential targets for immunotherapy, given their immunogenic properties despite the low mutational burden of ccRCC (ref: Jiang doi.org/10.1016/j.cell.2025.01.046/). Zhu et al. highlighted the dual role of NOTCH1 in liver cancer, where its expression correlates differently with tumorigenicity and immune checkpoint inhibitor responses based on sex, indicating a complex interplay between genetic factors and therapeutic outcomes (ref: Zhu doi.org/10.1158/2159-8290.CD-24-1883/). Frigault et al. reported on the efficacy of itacitinib in reducing cytokine release syndrome (CRS) associated with IEC therapy, demonstrating a significant reduction in severe CRS events compared to placebo, thus enhancing the safety profile of CAR T-cell therapies (ref: Frigault doi.org/10.1182/blood.2024026586/). These findings collectively underscore the potential of leveraging bacterial and viral mechanisms to enhance immune responses against tumors.

The combination of radiotherapy and immunotherapy is emerging as a promising strategy to enhance anti-tumor responses. Chen et al. demonstrated that low-dose irradiation of the gut can significantly improve the efficacy of PD-L1 blockade in metastatic cancer patients, suggesting that the gut's immune environment plays a crucial role in mediating these effects (ref: Chen doi.org/10.1016/j.ccell.2025.02.010/). Liu et al. further explored this synergy in triple-negative breast cancer, revealing distinct immune activation patterns when combining PD-L1 inhibitors with different chemotherapy agents, thus emphasizing the importance of treatment combinations in optimizing immune responses (ref: Liu doi.org/10.1016/j.ccell.2025.02.016/). Lubrano et al. identified the activation of focal adhesion signaling as a resistance mechanism in BRAF V600E melanoma, proposing that combining FAK inhibitors with RAF-MEK therapies could enhance treatment efficacy (ref: Lubrano doi.org/10.1016/j.ccell.2025.02.001/). Wu et al. investigated the synergistic effects of anti-TGF-β/PD-L1 bispecific antibodies with radiotherapy, demonstrating improved antitumor immunity and reduced radiation-induced pulmonary fibrosis, thus highlighting the potential for combination therapies to overcome resistance and enhance patient outcomes (ref: Wu doi.org/10.1186/s13045-025-01678-2/).

Biomarkers and predictive models are critical for optimizing immunotherapy outcomes. Shah et al. proposed that metabolic reprogramming of immune cells is essential for effective immune responses, suggesting that extracellular and intracellular metabolites could serve as biomarkers for immunotherapy efficacy (ref: Shah doi.org/10.1038/s42255-025-01241-w/). Tang et al. investigated the role of stromal stiffness-regulated IGF2BP2 in pancreatic cancer, linking m6A modification to immune evasion and proposing strategies for clinical intervention based on these findings (ref: Tang doi.org/10.1053/j.gastro.2025.03.019/). Falgàs et al. characterized the expression of immune checkpoint receptors in B-cell acute lymphoblastic leukemia, revealing that TIM-3 expression in CAR T-cells negatively correlates with clinical outcomes, thus providing insights into potential predictive biomarkers (ref: Falgàs doi.org/10.1182/blood.2024025440/). Additionally, Ma et al. explored genetic and epigenetic mechanisms of GPRC5D loss in multiple myeloma post-CAR T-cell therapy, shedding light on resistance mechanisms that could inform future biomarker development (ref: Ma doi.org/10.1182/blood.2024026622/).

Single-cell and genomic analyses are revolutionizing our understanding of cancer immunotherapy. Liu et al. applied single-cell RNA and TCR sequencing to analyze immune heterogeneity in NSCLC patients treated with anti-PD-1 therapy, revealing significant variability in immune responses that could inform personalized treatment strategies (ref: Liu doi.org/10.1016/j.cell.2025.03.018/). Li et al. leveraged a clinical trial to compare various neoadjuvant therapies in head and neck squamous cell carcinoma, finding that combination therapies resulted in higher pathologic response rates and better survival outcomes, thus emphasizing the value of multi-faceted treatment approaches (ref: Li doi.org/10.1016/j.ccell.2025.02.026/). Wen et al. conducted a phase 1 clinical trial exploring multimodal standard care and combined immunotherapies for glioblastoma, aiming to assess safety and immune activation metrics that correlate with clinical outcomes (ref: Wen doi.org/10.1093/neuonc/). Additionally, Yang et al. investigated the impact of CREBBP mutations on enhancer activation in lymphomas, suggesting that genetic alterations can significantly influence treatment responses and outcomes (ref: Yang doi.org/10.1182/blood.2024026664/).

Adoptive cell transfer and T cell engineering are at the forefront of cancer immunotherapy advancements. Yang et al. studied the effects of CREBBP mutations in lymphomas, revealing that enforced CD4 T-cell engagement can restore blunted enhancer activation, thus enhancing therapeutic efficacy (ref: Yang doi.org/10.1182/blood.2024026664/). Wang et al. explored the immunosuppressive role of JAG2 in tumor-associated neutrophils, suggesting that targeting this pathway could improve immune responses in high-grade serous ovarian cancer (ref: Wang doi.org/10.1002/cac2.70021/). Falgàs et al. characterized the expression of immune checkpoint receptors in B-cell acute lymphoblastic leukemia, finding that TIM-3 expression negatively correlates with clinical outcomes, indicating potential targets for improving CAR T-cell therapy (ref: Falgàs doi.org/10.1182/blood.2024025440/). Frigault et al. demonstrated that itacitinib significantly reduces the incidence of severe CRS in patients undergoing IEC therapy, highlighting the importance of managing side effects to enhance the efficacy of adoptive cell therapies (ref: Frigault doi.org/10.1182/blood.2024026586/).