The development of effective immunotherapies

The gap

Evidence profile

Sourced from the stated challenges and future work and open questions of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 4 journals. Those papers have been cited 144 times in total.

Supporting evidence — 4 representative gaps

• uPAR-directed immunotherapies in solid tumors: current advances and future perspectives (2026) · Frontiers in Pharmacology · doi

  The development of effective immunotherapies that can target uPAR without causing substantial toxicity to healthy tissues. The need to overcome the limitations of current immunotherapies, including incomplete tumor eradication and treatment resistance. The challenge of identifying suitable tumor-associated antigens and developing strategies that can simultaneously target tumor cells and the supportive tumor microenvironment.

  generalstated challenges
  Keywords: development effective immunotherapies target upar causing substantial toxicity
• Immunotherapy for pediatric solid tumors: overcoming biological barriers through rational multimodal combinations (2026) · Cancer Immunology Immunotherapy · 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.

  generalfuture workevidence 5/5
  Keywords: immunotherapy tumors responses cell tumor pedi atric solid generation platforms clinical malignancies barriers therapeutic neoantigen
• Breakthrough of solid tumor treatment: CAR-NK immunotherapy (2024) · Cell Death Discovery · cited 144× · 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 characteristics, is termed ‘immune escape’. 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. 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 enhancing NK cells’ specific killing effect on target cells. 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.

  generalopen questionsevidence 5/5
  Keywords: cells zhengzhou tumor immune hospital cancer solid liated university china tumors department there whether antigen
• Rethinking PDAC: from immunological silence to therapeutic opportunity (2026) · Frontiers in Immunology · doi

  Future research in PDAC immunotherapy should focus on rational combination strategies that simultaneously target tumor- intrinsic oncogenic signaling, stromal barriers, and immune sup- pression. Integrating multi-omics, single-cell, and spatial profiling with protein-protein interaction (PPI) network analysis will be critical for identifying predictive biomarkers that enable patient stratification and guide personalized treatment (116, 117). Particular emphasis should be placed on restoring antigen presen- tation, enhancing T-cell trafficking, and reprogramming immuno- suppressive myeloid and stromal compartments. Furthermore, combining KRAS inhibitors with ICB therapies warrants further research to address the immune-cold TME typical of PDAC (118– 120). Early-phase clinical trials incorporating immune modulation with chemotherapy, targeted therapies, or neoantigen-based vac- cines, alongside biomarker-driven endpoints, will be essential for improving response durability and clinical outcomes. Together, these efforts may transform PDAC from an immunologically “cold” tumor into one that is responsive to immunotherapy.

  generalfuture workevidence 5/5
  Keywords: pdac immune immunotherapy tumor stromal cell protein therapies cold clinical future focus rational combination strategies

Questions about this gap