Smart drug delivery systems to overcome drug resistance in cancer immunotherapy

The paper addresses the central challenge that, despite the transformative impact of cancer immunotherapies (including vaccines, cell therapy, immune checkpoint inhibitors, therapeutic antibodies, and small-molecule inhibitors), clinical response rates—particularly for immune checkpoint blockade—remain low due to drug resistance. Tumor-intrinsic factors (e.g., PD-L1 overexpression, IDO-1 activity, altered uptake/efflux, target mutations, reduced antigenicity/MHC-I expression, IFN pathway dysregulation, oncogenic signaling) and tumor-extrinsic factors within the immunosuppressive microenvironment (e.g., Tregs, MDSCs, TAMs, TANs, acidic/hypoxic metabolism, suppressive checkpoints) hinder efficacy. Smart drug delivery systems (SDDSs), leveraging stimuli-responsive materials and precise targeting, are proposed to overcome these resistance mechanisms by: increasing intratumoral drug accumulation, inducing immunogenic cell death (ICD), reprogramming immune cells, remodeling the TME, and modulating key signaling pathways. The review outlines resistance mechanisms and details SDDS strategies to counter them, concluding with challenges and future directions for translation.

The authors situate their review within prior work on SDDSs and cancer nanomedicine, noting that earlier reviews highlighted SDDS-enabled immunotherapy but did not specifically focus on overcoming immunotherapy resistance. They synthesize extensive literature on resistance types (primary, adaptive, acquired) and mechanisms (intrinsic and extrinsic), and collate recent SDDS advances that: co-deliver ICD inducers with IDO-1 or checkpoint inhibitors; regulate cholesterol metabolism; target immunosuppressive cells (MDSCs, TAMs) and ECM/stromal barriers; modulate metabolic microenvironments (acidity, hypoxia, lactate); activate or control IFN/STING signaling; restore PTEN function; and enhance ACT via cell-surface nanoconjugates and payload “backpacks.” The review aggregates preclinical evidence across multiple platforms (nanoparticles, liposomes, polymers, biomimetic carriers) and modalities (PDT/PTT, chemotherapy, mRNA, siRNA, protein drugs), emphasizing combinatorial regimens that address multiple resistance nodes.

- SDDSs inducing ICD and combination strategies: - Co-delivery of ICD inducers (e.g., oxaliplatin, photosensitizers) with IDO-1 inhibitors via TME-activated or Boolean logic nanoparticles synergistically increases CTL infiltration and reverses IDO-1-mediated suppression, improving antitumor immunity. - MMP-2-sensitive nanoparticles co-delivering anti-PD-L1 and ICG achieve PDT-induced ICD and checkpoint blockade with enhanced intratumoral CTL infiltration; bispecific assemblies (ICG+JQ1+BMS986205) induce ICD while reversing PTT-triggered PD-L1/IDO-1 upregulation, promoting strong CTL responses and immunologic memory. - Modulating cholesterol metabolism (e.g., avasimibe-loaded nanovesicles with MMP-2-responsive iRGD and PPa) restores CD8+ T cell function and enhances PDT-triggered ICD. - Reversing immunosuppressive TME: - Targeting suppressive cells: sHDL carriers loaded with STING agonist and gemcitabine selectively kill M2 TAMs, reduce MDSCs, promote DC maturation and M1 polarization, elevating IL-12 and reducing IL-10; biomimetic nano-RBC systems target CD163+ TAMs, decrease IL-10/TGF-β, increase IFN-γ, and boost CTL activity. Local in situ generation of CAR macrophages transforms M2 into M1-type and clears GSCs, enhanced by anti-CD47. - ECM/stroma remodeling: Photothermal bLPs disrupt stromal barriers, increasing secondary nanoparticle accumulation 4.27-fold and cancer cell accessibility 27.0-fold, inhibiting lung metastasis by 97.4%; pH-responsive DEX-HAase degrades HA to improve oxygen/drug penetration and augments PDT plus PD-L1 blockade; selective CAF targeting (Pin1 inhibition) reduces stromal barrier with less ECM damage. - Metabolic TME modulation: CaCO3 nanoparticles neutralize acidity and co-deliver DOX and aNLG919; siLdha VNPs reduce lactate production to reverse acidity and potentiate anti-PD-1 therapy; MnO2 nanoparticles catalyze H2O2 to O2, alleviate hypoxia/acidosis, enhancing radiotherapy; RBC-based oxygen delivery augments PDT. - Regulating IFN/STING and PTEN pathways: - SDDSs deliver and spatiotemporally control STING agonists (cGAMP/CDNs) via acid-responsive nanovaccines, endosomolytic polymersomes, ultrasound-microbubble nanocomplexes, and PEG-lipid nanodiscs, boosting DC IFN-I production, antigen presentation, and synergizing with PD-L1 blockade. - Epigenetic nanoinducers (e.g., ORY-1001-loaded, T cell membrane-coated) upregulate intratumoral IFNs, MHC-I, and PD-L1, then neutralize PD-L1 upon subsequent dosing to enhance CTL recruitment and activity. - PTEN restoration via modified mRNA delivered by polymer–lipid hybrid nanoparticles or ApoE-modified pH-responsive RBC membrane-coated systems crosses the BBB for glioblastoma, reversing PTEN loss-associated resistance and enhancing antitumor immunity. - Enhancing ACT efficacy: - TCR-signaling-responsive protein nanogels (IL-15 superagonist) anchored to T cells enable intratumoral expansion (~16-fold over systemic IL-15Sa) while minimizing peripheral activation. - Metabolic backpacks (avasimibe liposomes) tethered to T cells modulate membrane cholesterol to facilitate TCR clustering and sustain activation. - Macrophage IFN-γ-loaded shape-engineered backpacks maintain M1 phenotype within tumors and reprogram endogenous TAMs. - NK cell backpacks with IL-12 and bioorthogonal targeting enhance NK proliferation, activation, homing, and cytotoxicity; IS-triggered DOX release from NK cell-conjugated micelles augments killing. - CAR-T cells equipped with hyaluronidase and anti-PD-L1 bypass ECM barriers and local checkpoint inhibition, improving solid tumor infiltration and function.

The review demonstrates that SDDSs can mechanistically address both tumor-intrinsic and -extrinsic determinants of immunotherapy resistance by: (1) amplifying antigen release/exposure via ICD to overcome poor antigenicity and enhance T cell priming; (2) blocking suppressive pathways (PD-1/PD-L1, IDO-1) and correcting dysfunctional metabolism (cholesterol, lactate, acidity, hypoxia) to restore effector cell functionality; (3) reprogramming the cellular composition of the TME (reducing MDSCs/TAMs, promoting M1 polarization, degrading stromal barriers) to facilitate drug and immune cell penetration; (4) restoring or leveraging key signaling axes (IFN/STING, PTEN) to enhance antigen presentation and T cell infiltration; and (5) functionally augmenting adoptively transferred immune cells to resist immunosuppression and improve trafficking. Collectively, these strategies suggest SDDSs are well-suited for multi-pronged, spatiotemporally controlled interventions that synergize with ICB and ACT to convert resistant tumors into responsive ones. The inclusion of quantitative enhancements (e.g., stromal remodeling boosting accumulation and reducing metastasis; intratumoral cytokine delivery expanding T cells) underscores translational potential.

SDDSs offer versatile, stimuli-responsive platforms to overcome cancer immunotherapy resistance by: inducing ICD and combining with checkpoint/IDO-1 blockade or cholesterol modulation; remodeling immunosuppressive TMEs (targeting suppressive cells, ECM/stroma, and metabolic abnormalities); modulating IFN/STING and restoring PTEN; and enhancing ACT via immune cell-surface nanoconjugates and localized payload delivery. These approaches increase intratumoral drug concentration, restore/enhance effector cell function, and promote durable antitumor immunity. Future work should prioritize biocompatible/biodegradable materials, rigorous translational models (orthotopic/in situ, humanized systems), precise control over spatiotemporal release and targeting (especially to immune cells), and clinical strategies that integrate SDDSs with established immunotherapies to tackle heterogeneous resistance mechanisms.

- Material safety and immunogenicity: Some SDDSs use non-biodegradable components and materials with intrinsic immunomodulatory activity that may cause toxicity, excessive inflammation, or unintended resistance. - Translational gaps: Efficacy predominantly shown in murine, often subcutaneous models with cell lines that poorly recapitulate human tumor heterogeneity and TME complexity; species differences limit predictability. - Targeting paradigm: Simply encapsulating drugs for tumor cell uptake may be insufficient; preferentially delivering to and functionalizing immune cells may be more effective but requires precise targeting and control. - Potential risks of ECM remodeling: While enhancing penetration, ECM degradation may facilitate tumor cell intravasation and metastasis, necessitating strategies that minimize dissemination (e.g., selective CAF targeting). - Delivery challenges: Achieving deep penetration, endosomal escape (for nucleic acids/STING agonists), and controlled activation while avoiding off-target inflammation remains difficult.