Polymeric Systems for Cancer Immunotherapy: A Review

Purpose: Cancer immunotherapy — especially immune checkpoint inhibitors (ICIs), CAR-T cells, and oncolytic viruses (OVs) — has shown major clinical success but still faces low response rates, severe immune-related side effects, complex tumor microenvironment barriers, instability/short half-life of therapeutics, and high manufacturing costs. Polymeric systems are proposed as versatile carriers and immune-modulating platforms to improve targeting, safety, and antitumor efficacy.

Hypothesis: As a review, this paper does not test a single formal hypothesis. Its central premise is: if polymeric systems are used to deliver or modify immunotherapeutic agents — ICIs, CAR-T components, or oncolytic adenoviruses — then their therapeutic efficacy, biocompatibility, and tumor specificity can be improved while reducing systemic toxicity and off-target effects.

Aims: Review the monotherapy status and limitations of immune checkpoint inhibitors, CAR-T cells, and oncolytic viruses. - Describe current combination strategies between these immunotherapies and diverse polymeric systems. - Analyze polymeric systems for ICI delivery, including antibodies, siRNA, small-molecule inhibitors, micelles, nanoparticles, and microneedles. - Review polymeric platforms for CAR-T cell activation and genetic modification, including nanoscale/microscale artificial APCs and nonviral gene delivery. - Discuss polymer-based modification of oncolytic adenovirus to overcome CAR dependence, neutralizing antibodies, hepatotoxicity, and poor tumor targeting.

Delivery system: Polymeric carriers: nanoparticles, polymeric micelles, microparticles, hydrogels, microneedles, polyplexes, nanocomplexes, and artificial antigen-presenting cells (aAPCs). - Polymers: PEG-PLGA, PEG-PLA, PLGA, PCL, PEI, PBAE, PAMAM, pDMAEMA, chitosan, poly(isocyanopeptide), poly(CBA-DAH), PEG, polysaccharide matrices, and others. - Payloads: anti-PD-1/PD-L1 antibodies, anti-CTLA-4, IDO inhibitors (NLG919, indoximod, 1-MT), TGF-βRI inhibitor, siRNA (PD-L1, CTLA-4), chemotherapeutics (DOX, PTX), mRNA, plasmid DNA, CAR genes, oncolytic adenovirus, cyclic dinucleotides, and cytokines. - Targeting ligands: folate, anti-CD3, anti-CD8, anti-CD8a F(ab′)2, RGD/cRGD, MHC-Ig dimer, anti-CD28, and tumor-homing peptides. - CAR-T platforms: TransAct, semiflexible synthetic dendritic cells (sDCs), ellipsoidal PLGA aAPCs, carbon nanotube–polymer composites, supramolecular nanoparticles, and PBAE-mRNA/DNA nanocarriers. - Oncolytic adenovirus formulations: Ad/rPEI, Ad/DA3, Ad/PNLG, Ad/PPSA, PEGylated Ad, PAMAM-dendrimer-coated Ad, polyphenylene dendron–Ad complexes, Ad/CD-PEG-cRGD, Ad/chitosan-PEG-FA, and hydrogel co-delivery with dendritic cells.

Approach: Narrative literature review synthesizing preclinical and clinical studies. - In vitro models: various cancer cell lines (B16, 4T1, MCF-7, SKOV-3, HepG2, KB, A549, HT1080, etc.) and T-cell lines/primary T cells (Jurkat, human primary T cells). - In vivo models: mouse melanoma, breast cancer, colon carcinoma, leukemia, and xenograft tumor models. - Clinical context: FDA-approved ICIs (e.g., Yervoy), CAR-T products (Kymriah, Yescarta), and oncolytic viruses (Imlygic, Oncorine). - Rigor: No systematic review, meta-analysis, or primary group structure is provided; evidence is synthesized from cited primary studies.

Key methods: The review summarizes methods used in the cited primary studies rather than presenting new methods: - Nanoparticle characterization: size, zeta potential, morphology. - Cellular uptake, T-cell binding, and internalization: flow cytometry, confocal microscopy. - T-cell activation/proliferation and cytokine production. - Transfection efficiency and cell viability. - Tumor growth inhibition, survival, biodistribution, and imaging. - Viral transduction efficiency, CAR-independent internalization, and neutralizing antibody assays.

Key results: Representative findings highlighted in the review: - ICI delivery: Folate-PEI/PD-L1 siRNA blocked PD-1/PD-L1 interactions and reduced PEI cytotoxicity in ovarian cancer cells. PLGA-PEG nanoparticles targeted to CD8⁺ T cells delivered TGF-βRI inhibitor, reduced off-target toxicity, and restored T-cell function. Microneedle-delivered anti-PD-1 antibody produced stronger immune responses than free antibody at the same dose in a B16F10 melanoma model. - CAR-T engineering: PBAE-mRNA nanocarriers transfected >80% of primary T cells with mRNA within 2 h. In situ CD3-targeted PBAE-DNA nanocarriers bound 34% ± 5.1% of circulating T lymphocytes at 4 h, with off-target binding of 5.9% ± 2.8%; five doses of 3×10¹¹ nanoparticles programmed T cells and achieved tumor inhibition comparable to high-dose adoptive CAR-T transfer. - Oncolytic adenovirus: Ad/rPEI improved transduction in CAR-positive and CAR-negative cells; GFP expression was 7.7-fold higher in A549, 2.9-fold in HT1080, and 2.0-fold in MCF7 versus Ad/25 kDa PEI. Ad/PNLG showed a 1229-fold higher tumor-to-liver ratio than naked oAd. 20-kDa PEGylated oAd reduced hepatocyte transduction by 19- or 90-fold versus naked or 5-kDa PEGylated oAd and doubled average survival. - Combination hydrogel: Co-delivery of oncolytic adenovirus and dendritic cells in a gelatin-based hydrogel increased IL-12, GM-CSF, and IFN-γ levels, enhanced CD4⁺/CD8⁺ T-cell infiltration, and produced the best antitumor effect in the reviewed models.

Interpretation: The authors conclude that polymeric systems can overcome major limitations of ICIs, CAR-T, and oncolytic viruses by improving delivery, targeting, biocompatibility, and controlled release while protecting therapeutic bioactivity. They anticipate that next-generation polymeric platforms will be multifunctional, smart-responsive, and personalized, but emphasize that clinical translation still requires further whole-body biocompatibility and organ-level safety studies.

Limitations: This is a narrative review, not a systematic review or meta-analysis; no quantitative synthesis or risk-of-bias assessment is provided. - Most cited strategies remain preclinical; clinical translation is limited. - The review covers heterogeneous models, doses, and polymer systems, making direct comparisons difficult. - Key challenges remain: low treatment efficacy, immunotherapy resistance, patient safety, high cost, and scalable manufacturing. - The article is from 2022, so it may not include the most recent advances in polymeric cancer immunotherapy. - Conflict of interest: one author (C-OY) is CEO of GeneMedicine Co., Ltd., which may be relevant when interpreting translational claims.