Recent advancements in CAR T-cell therapy have focused on enhancing therapeutic specificity and efficacy, particularly for solid tumors. Kondo et al. engineered CAR T cells to co-express T cell receptors (TCRs), which improved their ability to distinguish between cancerous and healthy cells, thus enhancing specificity (ref: Kondo doi.org/10.1016/j.cell.2025.03.017/). Liu et al. introduced sonogenetic EchoBack-CAR T cells, which utilize a heat-shock promoter to maintain CAR expression upon ultrasound stimulation, demonstrating significant cytotoxicity against glioblastoma in 3D models (ref: Liu doi.org/10.1016/j.cell.2025.02.035/). In contrast, Zhong et al. highlighted the challenge of CAR T cell fratricide due to extracellular vesicles secreted by solid tumors, which can lead to reduced efficacy of CAR T therapies (ref: Zhong doi.org/10.1038/s43018-025-00949-8/). Furthermore, Lei et al. reported promising results from a phase 1 trial of 4-1BB co-stimulated CAR-NK cells in large B cell lymphoma, indicating a safe and feasible approach with a median progression-free survival of 9.5 months (ref: Lei doi.org/10.1038/s43018-025-00940-3/). These studies collectively underscore the need for innovative strategies to overcome the limitations of CAR T-cell therapies in solid tumors and enhance their clinical applicability.

The tumor microenvironment (TME) plays a critical role in immune evasion, particularly in the context of metastatic disease. Cheng et al. demonstrated that bone metastases can induce resistance to immune checkpoint blockade therapies in extraosseous tumors through osteopontin-producing osteoclasts, highlighting a mechanism of long-distance communication that dampens immune responses (ref: Cheng doi.org/10.1016/j.ccell.2025.03.036/). Additionally, Cui et al. identified tumor-derived CD109 as a key factor in reprogramming tumor-associated macrophages, which further contributes to immune suppression in intrahepatic cholangiocarcinoma (ref: Cui doi.org/10.1016/j.jhep.2025.03.035/). The study by Tzeng et al. also emphasized the metabolic alterations in the TME, where CD36 upregulation in tumor-infiltrating immune cells leads to impaired antitumor immunity (ref: Tzeng doi.org/10.1158/2159-8290.CD-24-1409/). These findings illustrate the complex interplay between tumor cells and the immune system within the TME, necessitating novel therapeutic strategies to counteract immune evasion.

The identification of predictive biomarkers is crucial for optimizing treatment responses in cancer therapy. Valenza et al. conducted a systematic review and meta-analysis demonstrating that circulating tumor DNA (ctDNA) clearance is a strong predictor of pathologic complete response in patients treated with neoadjuvant immune checkpoint inhibitors, with a pooled sensitivity of 0.98 (ref: Valenza doi.org/10.1016/j.annonc.2025.03.019/). In another study, Grover et al. evaluated the efficacy of adjuvant therapy in stage IIIA cutaneous melanoma, reporting a 2-year relapse-free survival rate of 79.3% for anti-PD-1 therapy (ref: Grover doi.org/10.1016/j.annonc.2025.03.021/). Furthermore, Xing et al. provided insights into brain metastases through single-cell RNA sequencing, revealing distinct cellular states that may inform treatment strategies (ref: Xing doi.org/10.1016/j.ccell.2025.03.025/). These studies highlight the importance of integrating biomarker discovery with clinical outcomes to enhance personalized treatment approaches.

Combination strategies in immunotherapy are gaining traction as a means to enhance treatment efficacy. Schaeffeler et al. discussed the potential of personalized cancer vaccines, emphasizing the need for tailored approaches in renal cancer (ref: Schaeffeler doi.org/10.1038/s41392-025-02204-z/). Wermke et al. presented interim results from a trial of TCR-engineered T cells targeting PRAME, which showed promise in treating solid tumors (ref: Wermke doi.org/10.1038/s41591-025-03650-6/). Qi et al. explored the combination of rituximab with therapeutic vaccines for non-Hodgkin lymphoma, demonstrating superior tumor suppression and relapse prevention in humanized mouse models (ref: Qi doi.org/10.1002/adma.202502372/). Additionally, Huang et al. investigated the role of preventing efferocytosis in tumor-associated macrophages, finding that blocking this process could enhance antitumor immunity (ref: Huang doi.org/10.1021/jacs.5c05640/). These findings underscore the potential of combining various therapeutic modalities to improve patient outcomes.

Innovative therapeutic approaches are essential for advancing cancer immunotherapy. George et al. identified nucleophosmin (NPM1) as a promising target for acute myeloid leukemia, revealing its role as a surface protein that could be exploited for immunotherapy (ref: George doi.org/10.1038/s41587-025-02648-2/). Shen et al. highlighted the role of Alcaligenes faecalis in inducing intestinal T helper-17 cells, suggesting a novel microbiota-based strategy for enhancing immune responses (ref: Shen doi.org/10.1016/j.immuni.2025.03.008/). The DGlyTAC technique developed by Li et al. offers a targeted approach to inactivate immune checkpoint proteins by removing N-glycans, showing promise in enhancing anti-cancer immunity (ref: Li doi.org/10.1038/s41392-025-02219-6/). These studies illustrate the potential of novel strategies to overcome existing barriers in cancer treatment and improve therapeutic efficacy.

Cancer vaccination and immune modulation are critical components of contemporary cancer therapy. Martín-Lluesma et al. conducted a systematic review on the safety of adoptive therapy with tumor-infiltrating lymphocytes combined with high-dose interleukin-2, emphasizing the need to manage treatment-related adverse events effectively (ref: Martín-Lluesma doi.org/10.1016/j.annonc.2025.04.001/). Shen et al. further explored the role of gut microbiota in modulating immune responses, demonstrating that Alcaligenes faecalis can induce T helper-17 cells, which may enhance anti-tumor immunity (ref: Shen doi.org/10.1016/j.immuni.2025.03.008/). The DGlyTAC technique developed by Li et al. represents a novel method for selectively targeting immune checkpoints, potentially improving the efficacy of cancer vaccines (ref: Li doi.org/10.1038/s41392-025-02219-6/). These findings highlight the importance of integrating vaccination strategies with immune modulation to enhance therapeutic outcomes.

Clinical trials play a pivotal role in evaluating treatment outcomes and advancing cancer therapies. Menghini et al. investigated the role of DR3 signaling in the generation of pathogenic T helper 9 cells in Crohn's disease, providing insights into immune regulation that could inform therapeutic strategies (ref: Menghini doi.org/10.1053/j.gastro.2025.03.035/). Tzeng et al. reported on the efficacy of PLT012, a humanized CD36-blocking antibody, in unleashing antitumor immunity against liver cancer, highlighting the importance of targeting metabolic pathways in the TME (ref: Tzeng doi.org/10.1158/2159-8290.CD-24-1409/). Additionally, Li et al. synthesized chiral aluminum oxyhydroxide supraparticles as adjuvants, which could enhance vaccine efficacy (ref: Li doi.org/10.1002/adma.202504458/). These studies underscore the significance of clinical trials in shaping future cancer treatment paradigms.

Tumor-associated macrophages (TAMs) are critical players in the tumor microenvironment, influencing immune responses and treatment outcomes. Cui et al. identified CD109 as a tumor-derived factor that reprograms TAMs to dampen immune responses in intrahepatic cholangiocarcinoma, suggesting a potential therapeutic target (ref: Cui doi.org/10.1016/j.jhep.2025.03.035/). Tzeng et al. further explored the metabolic adaptations of TAMs, revealing that CD36 upregulation impairs antitumor immunity by promoting the survival of regulatory T cells while rendering CD8+ T cells more susceptible to exhaustion (ref: Tzeng doi.org/10.1158/2159-8290.CD-24-1409/). Additionally, Kranendonk et al. examined the variability of B7-H3 expression in pediatric high-grade CNS tumors, which may impact the effectiveness of targeted therapies (ref: Kranendonk doi.org/10.1093/neuonc/). These findings highlight the complex role of TAMs in cancer progression and the need for strategies to modulate their activity for improved therapeutic outcomes.