In advanced melanoma, the immunosuppressive TME dominated by TGF-β severely limits therapeutic efficacy. While lipid-calcium-phosphate (LCP) NPs showed early promise in antigen delivery for primary melanoma, their efficacy in late-stage disease was constrained by TGF-β-mediated immune suppression (93). To address this, lipid-polyarginine-hyaluronic (LPH) acid NPs were engineered to co-deliver TGF-β siRNA and LCP vaccines. This dual-action strategy silenced immunosuppressive signals while enhancing antigen presentation, significantly improving antitumor responses in advanced melanoma models (93).

Antigen encapsulation efficiency and MHC-restricted immune activation are critical for vaccine efficacy. Zinc-chelating lipid-coated zinc phosphate hybrid NPs (LZnP NPs) leverage zinc’s coordination properties to achieve >90% peptide loading efficiency. Their lipid bilayer enhances colloidal stability and biocompatibility, while the hybrid core promotes cross-presentation via MHC class I/II pathways, broadening T cell responses across diverse HLA haplotypes (94). Building on this, a hexavalent melanoma vaccine encapsulated in immunogenic nanoliposomes with TLR4 agonist KDO2 demonstrated enhanced CD8⁺/CD4⁺ T cell priming. This design overcame peptide instability and drug resistance, synergizing with checkpoint inhibitors to prolong survival (95).

Lipid-based systems enable spatiotemporal control of chemoimmunotherapy. For example, IL-13-functionalized long-circulating liposomes (IL-13-LCL-SIM) and PEGylated extracellular vesicles (PEG-EV-DOX) were designed to disrupt crosstalk between tumor-associated macrophages (TAMs) and melanoma cells. IL-13-LCL-SIM selectively depleted protumoral M2-TAMs, while PEG-EV-DOX delivered doxorubicin (DOX) to tumor cells, inducing oxidative stress and apoptosis. This dual targeting reshaped the TME and suppressed metastatic progression (96). Similarly, a transdermal LPPC-DOX-CpG nanocomplex combined cationic liposomes (LPPC), DOX, and CpG ODNs. This system activated antigen-presenting cells (APCs) and cytotoxic T lymphocytes (CTLs), inhibiting both primary and metastatic lesions in visceral organs (97).

Recent advances integrate lipid NPs with immunogenic cell death (ICD) inducers. The pLCGM-OVA nanoagonist co-delivers Cu/Mn ions and ovalbumin antigen, responding to acidic TME for controlled release. Cu ions induce ROS-mediated cuproptosis, while Mn ions activate the cGAS-STING pathway, amplifying DC maturation and CTL infiltration. Remarkably, pLCGM-OVA’s intrinsic MRI T1 contrast enabled real-time monitoring of therapeutic responses, exemplifying a theranostic paradigm (98).

PNPs excel in delivering immune-stimulating payloads to activate innate and adaptive immunity. For instance, tobacco mosaic virus (TMV)-based PNPs co-loaded with the TLR-7 agonist 1V209 and photothermal polydopamine (PDA) achieved synergistic photothermal-immunotherapy. Under laser irradiation, the 1V209-TMV-PDA system induced localized hyperthermia for tumor ablation while triggering systemic antitumor immunity, marked by elevated tumor-specific CD8⁺ T cells and prolonged survival in melanoma-bearing mice (99). Complementing this, a thermosensitive hydrogel combining nano-hydroxyapatite (nHA) and GM-CSF demonstrated dual immunomodulation: nHA selectively induced tumor cell apoptosis via calcium overload, while GM-CSF amplified DC recruitment and antigen presentation. This combination outperformed monotherapies, highlighting the potential of PNPs to orchestrate spatially controlled immune activation (100).

The cyclic dinucleotide c-di-GMP, a potent STING pathway activator, was effectively delivered using peptide nanotube (PNT)-based PNPs. The c-di-GMP-PNT complex enhanced cytosolic STING activation in APCs, resulting in robust type I interferon production and CD8⁺ T cell-mediated tumor suppression. Notably, this strategy not only controlled primary melanoma but also inhibited metastatic spread, underscoring its systemic immunomodulatory capacity (101). Further advancing combination therapy, bioengineered nanogels (CDNPs) co-encapsulating BRAF and COX2 inhibitors induced melanoma cell pyroptosis—a highly ICD mode. When combined with anti-PD-1 antibodies, CDNPs synergistically enhanced CTL infiltration and tumor regression, providing a blueprint for overcoming ICB resistance (102).

PNPs are uniquely suited to dismantle immunosuppressive networks within the TME. The Ato/cabo@PEG-TK-PLGA system, administered via dual transdermal and intravenous routes, targeted MDSCs through localized hydrogen peroxide (H2O2)-triggered release of atovaquone and cabozantinib. This approach suppressed MDSC-mediated T cell inhibition while synergizing with photodynamic therapy (PDT) to eradicate primary tumors and prevent metastasis (103). Similarly, fluorocarbon-modified chitosan (FCS) NPs loaded with poly(I:C) reprogrammed the TME by activating DCs and enhancing CD8⁺ T cell priming. When paired with anti-PD-1 therapy, this system significantly improved checkpoint inhibitor efficacy, demonstrating PNPs’ ability to convert “cold” tumors into immunogenic niches (104).

A breakthrough in macrophage-centric therapy was achieved using poly-metformin-based carboxymethyl chitosan (PolyMetCMCS) nanogels. These PNPs selectively promoted M1 macrophage polarization via STAT3/NF-κB pathway modulation, which in turn activated DC maturation and cytotoxic T cell recruitment. In postsurgical melanoma models, PolyMetCMCS nanogels not only inhibited residual tumor growth but also established long-term immunological memory, preventing recurrence—a critical advancement for adjuvant immunotherapy (105).

In BRAF-mutant melanomas, Wnt5a overexpression drives stromal fibrosis and DC tolerization, creating an immune-excluded TME. To reverse this immunosuppressive axis, trimeric trap proteins were engineered to sequester Wnt5a and delivered via PNPs. This approach neutralized Wnt5a’s pro-fibrotic effects, restoring DC functionality and enabling CTL infiltration. When combined with low-dose DOX—a chemotherapy agent that induces ICD—the trapped Wnt5a-PNP system synergistically enhanced tumor antigen release and cross-presentation. Preclinical studies demonstrated that this dual-action strategy not only suppressed primary tumor growth but also established systemic immune memory, significantly improving survival in aggressive melanoma models (106).

Epigenetic silencing of the Fas death receptor in melanoma cells allows them to evade CTL-mediated apoptosis. To overcome this resistance, lipid-protein hybrid NPs (LPNs) were designed to deliver plasmid DNA encoding Fas (hCOFAS01). These PNPs efficiently transfected tumor cells, reinstating Fas expression and sensitizing melanoma to CTL attack. The restored Fas signaling cascade triggered tumor cell apoptosis while concurrently reprogramming the TME, as evidenced by increased CTL infiltration and reduced immunosuppressive cytokine levels. This gene-editing strategy highlights PNPs’ capacity to resurrect defective apoptotic pathways and reverse immune tolerance, providing a blueprint for restoring tumor cell susceptibility to immune elimination (107).

The CD47-SIRPα axis is a master regulator of macrophage-mediated immune evasion in melanoma. To disrupt this checkpoint, cyclic peptides mimicking the SIRPα-binding domain of CD47 were synthesized and delivered via PNPs. Engineered with a threonine-to-phenylalanine mutation (T/F variant), these cyclic peptides exhibited enhanced binding affinity for human SIRPα compared to linear counterparts. In human melanoma models, the peptide-PNP system competitively inhibited CD47-SIRPα interactions, thereby unleashing macrophage phagocytosis of tumor cells. Notably, the species-specific efficacy of these peptides—demonstrating higher activity in human cells than in murine systems—underscores their translational potential for clinical immunotherapy. This work exemplifies how PNPs can be tailored to block immune checkpoints and reactivate innate immune effector functions (108).

Iron oxide NPs, such as ferumoxytol (FMT), have emerged as potent tools for reprogramming TAMs. Functionalization of FMT with TLR3 agonist poly(I:C) (FMT-pIC) converted immunosuppressive M2-TAMs into tumoricidal M1 phenotypes, enhancing phagocytosis and pro-inflammatory cytokine secretion. This polarization disrupted stromal barriers and activated CTLs, significantly suppressing melanoma growth and metastasis. The therapeutic potential of iron oxides was further amplified in a nanovaccine formulation combining FMT with TLR4 agonist MPLA, which synergized with α-CD40 antibodies to induce tumor necrosis and systemic immunity in checkpoint inhibitor-resistant models (109).

Manganese-zinc sulfide (ZMS) NPs co-loaded with near-infrared dye IR780 exemplify the integration of chemodynamic therapy (CDT) and photothermal therapy (PTT). Under laser irradiation, ZMS-IR780 generated cytotoxic reactive oxygen species (ROS) via Fenton-like reactions while inducing localized hyperthermia. This dual action triggered ICD, releasing damage-associated molecular patterns (DAMPs) that activated DCs and promoted CTL infiltration. Concurrently, manganese ions released from ZMS activated the cGAS-STING pathway, amplifying type I interferon production and establishing durable antitumor immunity against both primary and metastatic lesions (110).

Redox-responsive magnetic nanocarriers (rMMNs) addressed ocular melanoma’s therapeutic resistance through glutathione-triggered release of miR-30a-5p, which silenced the oncogenic transcription factor E2F7 to suppress tumor proliferation. Simultaneously, iron ions within rMMNs polarized TAMs to M1 states, enhancing IL-6/IL-12 secretion and recruiting CTLs. In parallel studies, FMT-pIC NPs inhibited melanoma angiogenesis by downregulating VEGF and angiopoietin-2, disrupting endothelial cell networks and synergizing with macrophage-driven immune activation to create a hostile TME for tumor survival (111).

The folate-modified MOF NP TPL@TFBF demonstrated precision induction of ferroptosis and pyroptosis—two ICD modalities. By releasing Fe³⁺ and tannic acid in melanoma cells, TPL@TFBF initiated Fenton reactions for lipid peroxidation (ferroptosis) while activating gasdermin D-mediated pyroptosis. The resultant DAMPs, including ATP and HMGB1, recruited DCs and enhanced CD8⁺ T cell priming. When combined with anti-PD-1 therapy, this strategy achieved complete tumor regression in 40% of treated cases, showcasing MNPs’ ability to convert immunologically “cold” tumors into “hot” lesions (112).

While exosome-based cancer therapeutics require further clinical investigation, preclinical studies have demonstrated significant promise. Current immunotherapies, despite revolutionizing cancer treatment and improving survival rates in advanced cases, show limited efficacy against solid tumors compared to hematologic malignancies. This disparity stems from differential expression of immunoregulatory compounds that enhance immune cell interactions with hematological tumor cells (115).

The limited success of immunotherapy in solid tumors arises from several key challenges: The immunosuppressive and hypoxic TME impairs T cell proliferation, differentiation, and effector functions. Physical barriers (e.g., extracellular matrix, abnormal vasculature, cancer-associated fibroblasts) hinder immune cell infiltration and drug delivery while compromising T cell cytotoxicity. Immunosuppressive populations (MDSCs, Tregs, TAMs) within the TME actively suppress anti-tumor immunity (116).

For instance, while CTLA-4 inhibitors like ipilimumab enable 21% of patients to achieve 10-year survival and PD-1 inhibitors help 30% of advanced cancer patients survive beyond 5 years, these ICIs frequently cause immune-related adverse events (irAEs) (23). These limitations underscore the need for novel immunotherapeutic strategies with improved efficacy and safety profiles.

As master regulators of intercellular signaling, exosomes mediate complex communication networks between tumor and immune cells. They facilitate immune cell activation through interimmune signaling while simultaneously presenting tumor-associated antigens to counteract immune evasion (82). Their unique ability to penetrate tumor ECM and resist TME-mediated suppression makes them particularly promising for overcoming cell therapy limitations (83).

The ideal drug delivery system must ensure safety, efficacy, and proper biodistribution. While various platforms (micelles, nanoparticles, liposomes) have been explored (117), exosomes offer distinct advantages: Natural biocompatibility: Low immunogenicity and high stability. Enhanced targeting: Bioengineered exosomes can deliver payloads (chemotherapeutics, RNAs) specifically to tumor cells (118). Biological barrier penetration: Innate ability to traverse biological obstacles while avoiding lysosomal degradation, improving delivery efficiency (92). Cargo protection: The vesicular structure shields contents from degradation, enhancing stability. This unique combination of properties positions exosomes as exceptionally promising vehicles for next-generation cancer therapeutics.

A nanoscale artificial antigen-presenting cell (nano-aAPC) platform was developed to rapidly expand tumor-specific CD8⁺ T cells. Co-displaying MHC class I/peptide complexes and anti-CD28 antibodies, nano-aAPCs stimulated robust T cell proliferation ex vivo, generating high-affinity CTLs) capable of lysing PD-L1+ melanoma cells. These nano-aAPC-primed T cells showed enhanced persistence and efficacy when combined with anti-PD-1 therapy (123).

A TME-responsive nanocarrier co-delivering mitoxantrone (MIT) and celastrol (CEL) triggered dual ICD mechanisms: MIT induced DNA damage and calreticulin exposure, while CEL inhibited heat shock proteins to amplify DAMPs release. This strategy converted immunosuppressive TMEs into immunogenic niches, promoting DC activation and TIL recruitment, which synergized with ACT to induce tumor dormancy (124).

Prussian blue NPs (PBNPs) combined with near-infrared irradiation induced localized hyperthermia, eliciting ICD and upregulating co-stimulatory markers (CD80/86) on DCs. When paired with anti-CD137 antibodies, PBNP-PTT amplified CD8⁺ T cell effector functions and established immunological memory, achieving 90% suppression of melanoma recurrence (125).

Polymeric micelles loaded with sunitinib (SUNb-PM) reversed VEGF-driven immunosuppression by blocking STAT3 phosphorylation in TAMs. Concurrent delivery of a Trp2 peptide vaccine via mannose-modified LCP NPs enhanced antigen cross-presentation. This dual approach increased tumor-infiltrating CD8⁺ T cells by 3-fold and suppressed metastatic progression in late-stage melanoma (126).

Polymer-based NPs have been engineered to overcome PD-L1-mediated immune resistance. A study utilizing disulfide-crosslinked polyethyleneimine and trehalose sulfate NPs (siPD-L1/pd) demonstrated dual inhibition of PD-1/PD-L1 signaling and mTOR pathways. These NPs efficiently delivered PD-L1 siRNA to melanoma cells, silencing PD-L1 expression and reversing T cell exhaustion. In both immunocompetent and immunocompromised murine models, siPD-L1/pd NPs suppressed tumor growth and prolonged survival, highlighting their potential to restore antitumor immunity even in hosts with impaired immune systems (115).

Tetrahedral framework nucleic acid immunoadjuvants (FNAIAs) represent a breakthrough in transdermal immunotherapy. Composed of CpG oligodeoxynucleotide (ODN)-loaded DNA nanostructures, FNAIAs penetrate tumor tissues to activate DCs via TLR9 signaling. When co-loaded with DOX, the resulting DFNAIA nanocomplex induces ICD, releasing tumor-associated antigens that synergize with CpG ODN to trigger systemic antitumor immunity. In melanoma models, DFNAIA combined with anti-PD-1 antibodies not only eradicated local tumors but also suppressed distant metastases, demonstrating its capacity to convert localized therapy into systemic immune activation (116).

Paradoxically, nanotechnology can also exploit upregulated PD-L1 for therapeutic benefit. nHA was shown to transcriptionally enhance PD-L1 expression in melanoma cells via calcium-sensing receptor signaling. Leveraging this phenomenon, researchers developed an injectable nHA-incorporated hydrogel that co-delivers PD-1 inhibitors. The hydrogel acts as a sustained-release depot, promoting CD8⁺ T cell infiltration and polarization while blocking PD-1/PD-L1 interactions. This strategy not only inhibited primary tumor growth but also established long-term immune memory, offering a dual-target approach to enhance ICB efficacy (117).

A hydrazine/Cu/Fe/indocyanine green (TCFI) coordination nanocomplex exemplifies nanotechnology’s capacity to integrate multiple therapeutic modalities. Under near-infrared irradiation, TCFI exhibits Fenton-like, peroxidase-, and glutathione oxidase-like activities, inducing lipid peroxidation and ferroptosis. Concurrently, it alleviates hypoxia and depletes glutathione to amplify oxidative stress. When combined with anti-PD-1 therapy, TCFI significantly increased tumor-infiltrating CD8⁺ T cells and IFN-γ secretion, achieving robust suppression of primary tumors, lung metastases, and recurrence. This work underscores the potential of metal-based nanoplatforms to synergize ferroptosis with ICB (118).

In uveal melanoma (UVM), a redox-responsive nanocarrier co-delivering histone deacetylase inhibitor MS-275 and glutamine antagonist V-9302 was developed to overcome ICB resistance. The NPs exploit UVM’s high ROS levels to trigger ROS storms and pyroptosis—a proinflammatory cell death pathway. This approach transformed immunologically “cold” UVM into “hot” tumors by enhancing DC maturation and CTL infiltration. Combined with anti-PD-1 therapy, the system induced durable immune memory and suppressed metastatic progression, providing a blueprint for overcoming ICB resistance in refractory melanomas (119).

Erythrocyte membrane-camouflaged NPs exemplify the power of bioinspired design in vaccine delivery. These platforms utilize PLGA cores loaded with reduction-sensitive antigen peptides, cloaked in mannose-modified erythrocyte membranes to enhance lymphatic targeting and DC uptake. Preclinical studies demonstrated superior antigen cross-presentation and CTL activation compared to non-coated systems, achieving 60% suppression of metastatic melanoma progression (127). Building on this concept, Golgi-PD-L1-deficient exosome hybrid membrane-coated NPs (GENPs) mimic natural exosome trafficking to deliver tumor antigens directly to lymph node DCs. By evading PD-L1-mediated immune checkpoints, GENPs synergized with anti-PD-L1 therapy to reduce tumor recurrence and distant metastasis, highlighting their dual role as antigen carriers and immune checkpoint modulators (128).

The cowpea mosaic virus (CPMV) has emerged as a potent immunostimulant due to its intrinsic ability to activate pathogen recognition receptors. CPMV NPs selectively target S100A9-expressing metastatic niches in the lung, recruiting neutrophils and natural killer cells to establish premetastatic immunity. This approach not only prevented metastatic outgrowth but also eradicated established lesions, showcasing its potential as a prophylactic and therapeutic vaccine (129). A modified inactivated CPMV (inCPMV) platform further advanced safety without compromising efficacy. By engaging TLR2/4 signaling, inCPMV reprogrammed immunosuppressive microenvironments and synergized with OX40 agonistic antibodies to amplify CD8⁺ T cell infiltration, inducing systemic antitumor immunity even in non-treated tumors (130).

A breakthrough in carrier-free vaccine design was achieved through the spontaneous co-assembly of 2′-fluorinated CpG (2′F-CpG) and the melanoma neoantigen Obsl1. This system achieved near-complete antigen loading efficiency and leveraged size-dependent lymphatic drainage to target DCs in lymph nodes. The resulting nanovaccine triggered a 10-fold increase in neoantigen-specific CTLs compared to soluble antigens, establishing long-term immune memory against tumor rechallenge. This platform underscores the potential of minimalist nanovaccines for personalized immunotherapy (131).

Poly(β-amino ester) (PBAE) nanovaccines exemplify the synergy between antigen delivery and immune checkpoint modulation. By co-encapsulating Trp-2 antigen and TLR4 agonist MPLA, PBAE NPs primed DCs while PD-L1 blockade antibodies counteracted T cell exhaustion. This dual strategy converted immunologically “cold” melanomas into “hot” lesions, achieving complete regression in 40% of treated cases (132, 133). In fibrotic melanomas, sunitinib-loaded NPs (SUN-NPs) normalized dysregulated vasculature and depleted MDSCs, effectively “priming” the TME for subsequent vaccination. When combined with Trp-2/GalCer nanovaccines, SUN-NPs increased CTL infiltration 8-fold, demonstrating how nanotechnology can sequentially dismantle immunosuppressive barriers (134).

A lipid NP vaccine co-delivering α-galactosylceramide (GalCer) with melanoma antigens (Melan-A/gp100) and adjuvants (CpG/MPLA) leveraged the unique biology of invariant natural killer T (iNKT) cells. The lipid bilayer stabilized GalCer presentation to iNKT cells, which in turn activated DCs and amplified antigen-specific CTL responses. This approach reduced tumor volume by 90% and established protective immunity against recurrence, outperforming GalCer-free formulations (135).