BsADCs, embodying a “1 þ 1” model, represent a novel therapeutic class that amalgamates the strengths of ADCs and BsAbs. This fusion leverages the anti-tumor mechanisms of ADCs, while addressing clini

The gap

Consensus across the literature

Supporting evidence — 4 representative gaps

• Immunotherapy for pediatric solid tumors: overcoming biological barriers through rational multimodal combinations (2026) · doi

  Despite transformative advances in adult oncology and pedi- atric hematologic malignancies, immunotherapy for pedi- atric solid tumors faces distinct biological challenges that demand tailored solutions. Two fundamental barriers define this therapeutic landscape: exceptionally low TMB with sparse neoantigen generation, and profoundly immunosup- pressive TME dominated by myeloid suppressors, regulatory T cells, and stromal barriers that exclude effector cells and blunt therapeutic responses. The field has nonetheless achieved meaningful progress across multiple platforms. Anti-GD2 monoclonal antibodies have established a validated paradigm in high-risk neuro- blastoma, demonstrating that antibody-mediated cytotoxicity can improve survival when integrated into multimodal regi- mens. Next-generation antibody platforms, including B7-H3 and GD2-targeted ADCs, and bispecific T cell engagers, are  146 Page 16 of 20 Cancer Immunology, Immunotherapy (2026) 75:146 translating preclinical promise into early clinical trials, with engineered payloads and dual-targeting strategies addressing limitations of conventional antibodies. CAR T cell therapy has shown clinical activity against GD2, HER2, and B7-H3 targets, with locoregional delivery and advanced engineering (third-generation CARs, cytokine armoring, bispecific con- structs) enabling responses in select patients, though tumor infiltration, persistence, and antigen escape remain rate- limiting. ICIs, while largely ineffective as monotherapy in unselected populations, induce durable responses in molecu- larly defined subsets, hypermutated tumors, mismatch repair deficiency, and high TMB, establishing biomarker-driven selection as essential for rational ICI deployment. The future of pediatric solid tumor immunotherapy lies in rational combinations that simultaneously address multi- ple resistance mechanisms. Emerging data support integrat- ing TME modulators, oncolytic viruses, NK cell engagers, myeloid-reprogramming agents, and TGF-β inhibitors with ICI or cellular therapies to convert cold tumors into immu- nologically active lesions. Personalized neoantigen vac- cines combined with ICIs represent a compelling strategy to expand tumor-reactive T cell repertoires in otherwise non- immunogenic cancers. Critically, comprehensive immune profiling using spatial transcriptomics, multiplex imaging, and longitudinal immunomonitoring will be essential for stratifying patients, predicting responses, and guiding adap- tive treatment strategies. Realizing the full potential of immunotherapy in pedi- atric solid tumors requires continued investment in pediat- ric-specific trials, novel target discovery through system- atic antigen screening, optimization of delivery routes and dosing schedules, and mechanistic studies elucidating age- dependent immune ontogeny and tumor–host interactions. As platforms mature and combinations are refined through iterative clinical–translational cycles, immunotherapy stands poised to fundamentally alter outcomes for children with these historically refractory malignancies.

  Keywords: immunotherapy tumors responses cell tumor pedi atric solid generation platforms clinical malignancies barriers therapeutic neoantigen
• Cell-based cancer immunotherapy: milestones, mechanistic insights, and emerging therapeutic directions (2026) · doi

  Cell-based immunotherapies have emerged as a central compo- nent of contemporary oncology by enabling therapeutic mechan- isms that are difficult to achieve with conventional modalities, functional adaptability within including in vivo expansion, dynamic tumor ecosystems, and the potential for durable immune surveillance [120]. The clinical success of CAR T-cell therapy in hematologic malignancies has validated this paradigm and catalyzed the development of a broader spectrum of cellular tumor- platforms, infiltrating lymphocytes, NK cell–based therapies, dendritic cell vaccines, and macrophage-directed strategies [121–123]. Collec- tively, these approaches expand the scope of precision immuno- oncology by engaging complementary immune functions, includ- ing antigen-specific cytotoxicity, innate effector activity, antigen presentation and repertoire shaping, and active modulation of the tumor microenvironment. encompassing TCR–engineered T Despite this progress, the principal limitations of the field are now well defined. Antigen escape and heterogeneous target expression continue to compromise response durability, particu- larly for single-antigen strategies [30]. In solid tumors, immune exclusion, suppressive myeloid programs, metabolic constraints, and physical barriers collectively limit cellular trafficking, persis- tence, and effector function, even in the presence of tumor- In parallel, manufacturing remains reactive immune cells [124]. both a biological and logistical bottleneck; variability in starting material, prolonged vein-to-vein timelines, and high production costs restrict scalability and broad clinical access [125, 126]. These challenges indicate that future advances will depend less on incremental refinement of individual platforms and more on integrated strategies that simultaneously address target recogni- tion, cellular fitness, tumor accessibility, and safety. Several development priorities are likely to shape the next phase of cellular immunotherapy. Multiplex targeting and logic-gated designs provide promising solutions to antigen escape while improving on-target specificity [127]. Cell-state engineering—supported by optimized manufacturing condi- tions, epigenetic and metabolic conditioning, and precise genome editing—offers a pathway to enhanced persistence and resistance to exhaustion [128, 129]. Off-the-shelf approaches, including allogeneic donor–derived products and iPSC–based platforms, have the potential to reduce production timelines and improve scalability, provided that immune rejection and product consistency can be effectively controlled [53, 130, 131]. rational combination strategies are increasingly In addition, essential; likely require coordinated interventions integrate immune improved trafficking, and tumor microenvironment priming, modulation while maintaining an acceptable therapeutic index [132]. for many solid tumors, durable efficacy will that Acta Pharmacologica Sinica (2026) 0:1 – 18

  Keywords: tumor immune cell antigen cellular strategies based platforms target oncology therapeutic including potential durable clinical
• Breakthrough of solid tumor treatment: CAR-NK immunotherapy (2024) · doi

  Due to the recent proposal of CAR-NK therapy, there are currently very few CAR end designs available for reference, especially for solid tumors. It is unclear whether there is a universal design that is effective for all solid tumors or whether there is a specific optimal solution design for each solid tumor. Moreover, the current experimental sample size is generally too small and lacks integration. We need a large number of basic and clinical trials to verify and compare the effects of various CARs. Further validation is needed to determine whether CAR-NK can be widely applied in the treatment of solid tumors in clinical practice in the future. to survive and grow, INTRODUCTION Under normal circumstances, the immune system can identify and eliminate tumor cells within the Tumor microenvironment (TME). tumor cells employ diverse However, strategies to suppress the immune system, enabling their survival during different stages of the anti-tumor immune response. This phenomenon, where tumor cells exhibit the described character- istics, is termed ‘immune escape’ [1]. Tumor immunotherapy is a treatment method to control and eradicate tumors by combating immune escape and reinstating the body’s normal anti-tumor immune response. Chimeric antigen receptors (CARs) are fusion proteins, and the CAR structure of CAR-NK cells typically comprises three components: the extracellular antigen-binding region (usually scFv), the spacer and the transmembrane domain, and the intracellular activation domain. Natural Killer (NK) cells, as unique innate immune cells, display rapid and potent cytotoxicity for cancer immunotherapy and pathogen clearance without prior sensitization or antigen recognition [2]. CAR-NK cells are engineered to express CAR through genetic modification, connecting antibodies (or receptors) recognizing surface antigens of target cells (e.g. virus infected cells and cancer cells) with Signaling molecule required to activate immune cells. This modification can counteract inhibitory receptors, thereby enhan- cing NK cells’ specific killing effect on target cells [3]. For patients with solid tumor who are clinically advanced or extensively metastasized with poor responses to surgical and 1Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 2Department of Radiotherapy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. 3Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. 4Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 5Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. email: [email protected]; [email protected]; [email protected] ✉ Received: 24 November 2023 Revised: 4 January 2024 Accepted: 9 January 2024 Official journal of CDDpress 2 W. Wang et al. conventi

  Keywords: cells zhengzhou tumor immune hospital cancer solid liated university china tumors department there whether antigen
• Bispecific antibody drug conjugates: Making 1+1>2 (2024) · doi

  BsADCs, embodying a “1 þ 1” model, represent a novel therapeutic class that amalgamates the strengths of ADCs and BsAbs. This fusion leverages the anti-tumor mechanisms of ADCs, while addressing clinical challenges traditionally associated with ADCs through the versatility of BsAbs. BsADCs present a promising avenue for significantly enhancing the therapeutic efficacy of traditional ADCs, transcending conventional target and scaffold paradigms. Recent advancements have propelled BsADCs into phase I/II clinical trials, marking substantial progress in their development. Nevertheless, challenges persist, primarily attributed to the complexity of solid tumors, encompassing factors, compart- mental heterogeneity, histological disorder, and poor penetration. It is imperative to refine the design strategy of BsADCs to overcome these challenges. In this review, we encapsulate the latest design considerations and advances in BsADCs, with the goal of charting a course for future drug design. While existing progress is noteworthy, the continued development and application of BsADCs face unique challenges in the following aspects. 4.1. Broadening the antibody skeleton target selection for BsADCs remains somewhat

  Keywords: bsadcs adcs challenges design therapeutic bsabs clinical target progress development embodying model represent novel class