Hypoxia within tumors significantly reduces the effectiveness of various therapies, particularly radiation and PDT, both of which require sufficient oxygen to maximize cell-killing effects (Feldman, 2024). Recently, manganese dioxide (MnO₂)-based nanoparticles have emerged as effective agents to counter tumor hypoxia. MnO₂ catalyzes intratumoral hydrogen peroxide (H₂O₂) into oxygen (O₂), directly alleviating hypoxic conditions. Enhanced oxygenation sensitizes tumors to oxygen-dependent therapies and creates a more favorable environment for ICD by facilitating immune infiltration and ROS-mediated DAMPs release. Alleviating tumor hypoxia enhances ICD primarily by restoring oxygen-dependent cellular processes critical for DAMPs generation. For instance, improved oxygenation facilitates mitochondrial respiration and reactive oxygen species (ROS) generation, both of which are essential for triggering ER stress and subsequent exposure of CALR on the tumor cell surface—an established hallmark of ICD. Moreover, increased oxygen availability amplifies the efficacy of oxygen-dependent therapies like PDT, thereby intensifying ROS-mediated cell death and promoting the release of ATP and HMGB1 from dying tumor cells (Zeng et al., 2022a; Zeng et al., 2022b). Specifically, MnO₂ nanoparticles have shown enhanced radiation efficacy through the generation of stable DNA breaks, significantly promoting cancer cell apoptosis and subsequent ICD-associated DAMPs release (Prasad et al., 2014; Abbasi et al., 2016).

Another critical barrier in cancer immunotherapy is tumor acidity, which contributes to immune suppression and drug resistance (Bogdanov et al., 2022). Calcium carbonate (CaCO₃) nanoparticles effectively neutralize tumor acidity, thus significantly promoting dendritic cell (DC) activation and antigen presentation capability (Liang et al., 2023). Intratumoral injection of CaCO₃ nanoparticles not only directly suppresses tumor growth through local pH modulation but also facilitates DC maturation and enhances cytotoxic T lymphocyte (CTL) infiltration. This combination strategy markedly potentiates immune checkpoint blockade therapies, such as anti-PD-1 therapy, through reversing tumor immunosuppression and enabling more effective antigen-specific adaptive immune responses (Shan et al., 2020).

Nanomaterial-based strategies employing ROS induction have shown substantial promise in initiating potent ICD responses (Zhang et al., 2021). Nanoparticle-delivered photosensitizers precisely localize to tumor cells, generating robust and localized ROS production upon light irradiation, thus minimizing off-target toxicity and maximizing immune stimulation. Additionally, nanoparticles loaded with ferroptosis-inducing agents (e.g., RSL3) have demonstrated their ability to trigger ICD through lipid peroxidation, amplifying immune infiltration and improving anti-PD-1 treatment efficacy in preclinical models (Wang et al., 2022).

Recent advances have shown significant therapeutic benefits when nanomaterials-induced ICD is combined with established immunotherapeutic modalities (Demuynck et al., 2024). For instance, nanoparticles designed to alleviate tumor hypoxia or neutralize acidity have enhanced CAR-T cell therapy outcomes. Specifically, hypoxia-alleviating nanoparticles improve the persistence, functionality, and tumor-infiltrating capacity of CAR-T cells, significantly enhancing treatment efficacy in triple-negative breast cancer (TNBC) models (Dong et al., 2024). Furthermore, combining nanomaterial-driven ICD with immune checkpoint inhibitors (ICIs) has resulted in enhanced T-cell-mediated antitumor immunity, demonstrating strong therapeutic synergy and improved long-term immune memory responses (Qi et al., 2021). Similarly, osteosarcoma, a representative bone malignancy with poor immunogenicity, may benefit from nanomaterial-induced ICD strategies to overcome immune resistance and enhance responsiveness to checkpoint inhibitors or adoptive cell therapies (Hao et al., 2024). Recent evidence suggests that ICD-inducing nanomaterials, especially those coupled with adjuvants or checkpoint inhibitors, facilitate the formation of effector memory T cells and central memory T cells, providing long-term surveillance against tumor relapse. For instance, dual-delivery systems co-encapsulating oxaliplatin and CpG oligodeoxynucleotides have demonstrated robust memory T cell expansion and durable protection in murine tumor models (Deng et al., 2024).

Taken together, these representative cases underline the unique advantages of nanomaterials as versatile platforms capable of strategically modulating multiple tumor microenvironmental factors simultaneously. Such multi-modal approaches present new horizons for effective ICD induction, promising significant advancements in cancer immunotherapy.

One primary concern is the long-term safety and biocompatibility of nanomaterials. Chronic toxicity, off-target accumulation, and potential immunogenicity remain insufficiently addressed. Several nanoparticles, especially metal oxides and inorganic nanoparticles (e.g., MnO₂, CaCO₃), have raised concerns about potential chronic toxicity due to poor biodegradability or accumulation in vital organs (Zhang et al., 2022; Seabra et al., 2015). Thus, comprehensive long-term toxicity evaluations and strategies to improve biodegradability are essential prerequisites for clinical translation.

Another significant limitation is the absence of standardized methodologies for defining, quantifying, and validating ICD in nanomaterial-treated tumors. ICD is currently validated through variable combinations of biomarkers (CALR exposure, ATP secretion, HMGB1 release) and functional assays (vaccination assays, therapeutic immune responses). This variability complicates the comparative assessment across different nanomaterial platforms (Galluzzi et al., 2024; Galluzzi et al., 2020). Establishing consensus guidelines and standardized preclinical models to consistently assess ICD biomarkers and immune responses is urgently needed to accelerate translation into clinical practice.

Tumor heterogeneity remains a major obstacle, limiting the efficacy of ICD-based therapies. Intratumoral heterogeneity significantly influences responses to therapies, including ICD induction, due to variable expression of ICD markers, metabolic adaptations, and immune evasion mechanisms (Yan et al., 2025). Furthermore, tumors may develop resistance through upregulating immunosuppressive pathways (e.g., IDO1, PD-L1) or impairing antigen processing and presentation machinery. Strategies to overcome tumor heterogeneity and suppress immune escape require deeper mechanistic understanding and adaptive combination therapies.

Future research should emphasize the development of multifunctional nanoplatforms capable of simultaneously addressing multiple barriers within the TME. Integrated platforms capable of concurrent oxygen generation, acidity neutralization, redox modulation, and controlled drug release will provide synergistic enhancements in ICD induction and immune activation (Zhu et al., 2023; Luo et al., 2025). Emerging “smart” nanoplatforms, which can respond dynamically to tumor-specific triggers (e.g., low pH, hypoxia, enzyme overexpression), represent promising next-generation approaches.

Another promising direction involves precision nanomaterials engineered to selectively trigger specific cell death pathways such as ferroptosis, pyroptosis, or cuproptosis. Such selective cell death induction could enhance immunogenicity while minimizing off-target damage (Sahoo and Manna, 2025). For instance, ferroptosis-targeting nanoparticles can amplify ICD through selective lipid peroxidation, while pyroptosis-inducing platforms (e.g., gasdermin activators) can drive robust inflammasome activation and potent antitumor immunity (Wang et al., 2025).

Personalized and combinatorial strategies integrating ICD-inducing nanomaterials with established immunotherapies (e.g., ICIs, CAR-T, cancer vaccines) hold significant translational promise. Personalized ICD vaccines created from tumor-derived neoantigens combined with nanomaterials can achieve highly specific and effective antitumor responses (Yang et al., 2024). Moreover, the co-delivery of ICD inducers with checkpoint inhibitors and engineered immune cells may dramatically enhance therapeutic efficacy, immune memory, and clinical outcomes.