Introduction

Immunotherapy, which activates immune systems to combat cancer, has yielded considerable clinical benefits recently [1]. Antitumor immunotherapy can be typically divided into two categories based on the mechanism: (i) immune-enhancing therapies that reinforce immune responses against tumors, such as cytokines, vaccines, and adoptive cell therapy, and (ii) immune-normalizing therapies that repair the defects of systemic antitumor immunity, such as immune checkpoint blockade (ICB) [2]. Despite wide application in the clinic, how to obtain long-lasting responses in the majority of patients suffering cancer remains an unsolved problem for cancer immunotherapy [3].

Severe immune-related side effects (irSEs) and a low response rate hinder the progress of immunotherapy [4, 5]. The irSEs (e.g., myocarditis and pneumonia) result from nonspecific activation of the immune system due to the extratumoral distribution of the drug after systemic administration. Primary and acquired resistance in tumors results in the ineffectiveness of immunotherapy [6]. For instance, the objective response rates of programmed death 1 (PD-1) protein or its ligand (PD-L1) inhibitors against certain cancers (e.g., pancreatic cancer and glioblastoma) are lower than 30% [7]. The immunosuppressive tumor microenvironment (ITME) is a major hurdle to immunotherapy, as it supports tumor evasion of immune surveillance [8]. Therefore, develo** strategies to reverse the ITME is necessary for improving cancer immunotherapy [9, 10].

Nanosized drug delivery systems (NDDSs) improve the safety and efficacy of cancer immunotherapy because of their excellent pharmacokinetic and biodistribution profiles, including prolonged blood half-life, high intratumoral accumulation, and deep tumor penetration capacity [11,12,13]. They can also be designed as multidrug delivery platforms for combined therapy, which is beneficial for immunotherapy since ITME is an intricate network that requires modulation from multiple aspects [14,15,16].

Recently, our group reported a series of NDDSs for remodeling the ITME and enhancing cancer immunotherapy. In this review, we briefly introduce the composition of ITME and traditional treatments against ITME. Then, we will elaborate our endeavors in reversing the ITME to improve immunotherapy by manipulating NDDSs based on different strategies. Finally, the contributions and prospects of this field will be discussed.

Immunosuppressive tumor microenvironment

Characterization and composition

The tumor microenvironment (TME) is highly heterogeneous among tumors [17]. Based on the type, density and location of immune cells within the tumor site, the tumor immune microenvironment can be broadly classified into two categories: hot and cold tumors [18]. Immunologically hot tumors, with high infiltration of cytotoxic T lymphocytes (CTLs) and activation of the PD-1/PD-L1 signaling pathway, are responsive to immunotherapy [19]. Unfortunately, many tumors insensitive to immunotherapy are usually cold tumors with ITME, which are difficult to eradicate and associated with poor prognosis [20].

Multiple and complex factors contribute to the ITME. The low mutational burden and poor immunogenicity of tumors prevent recognition by the immune system [21, 22]. Various immunosuppressive cells and cytokines impede antitumor immune responses through different signaling pathways [23]. The extracellular matrix and chemokines of tumors block the penetration of antitumor immune cells [24, 25]. Both the physicochemical properties of the tumor, such as hypoxia [26] and weak acidity [27], and abnormal metabolic activities, such as the accumulation of adenosine [28] and increased metabolism of L-arginine [29], facilitate the immune escape of tumors.

Traditional immunomodulatory methods

A range of approaches have been developed based on the same goal: to enhance antitumor immunity. Since ITME is an outcome of the parallel occurrence of multiplex protumor mechanisms, combination therapies have the potential to harvest clinical benefits [30]. Immunogenetic cell death (ICD), induced by radiotherapy, phototherapy, and certain chemotherapeutic drugs, such as oxaliplatin, is a type of cell death accompanied by the release of damage-associated molecular patterns (DAMPs) [31]. Tumor cells undergoing ICD will mature dendritic cells (DCs) to cross-present tumor-associated antigens (TAAs) to CD4+ and CD8+ T cells and thus activate an adaptive immune response. In addition, released DAMPs promote phagocytosis and boost the innate immune response. Tumor vaccines or immune adjuvants can also transform cold tumors into hot tumors [32]. Targeted therapies to increase tumor immunogenicity [33], cytokine therapies to activate T cells [34], and oncolytic viruses to release TAAs [35] are potential strategies to propel immunotherapy as well.

However, traditional combination therapies also face the problem of undesired side effects and unsatisfactory efficiency. The nonspecific distribution of therapeutic agents after systemic administration causes damage to healthy organs and reduces the concentration and effects of the drug at the tumor sites. In addition, other therapies in combination with immunotherapy may affect the immune system, which limits the synergetic effects [36]. For instance, lymphodepletion and impact on tertiary lymphoid structures by chemotherapy may hinder the outcome of immunotherapy. The clinical responses of radioimmunotherapy combinations are contradictory since radiation kills tumor cells as well as immune effector cells. Therefore, strategies for targeted drug delivery are necessary to amplify the effects and reduce the toxicity of each component utilized in combination therapy.

NDDSs reversing ITME for enhancing cancer immunotherapy

NDDSs, with higher efficiency and safety than traditional treatments, can deliver immunomodulatory drugs specifically to tumor sites through passive or/and active targeting [37]. They can also be endowed with TME sensitivity to release payloads specifically at tumor sites, which further lessens adverse toxicities [38]. Moreover, multidrug-loaded nanoplatforms provide options for exerting the synergistic effects of combined treatments [39]. In this section, we will mainly introduce the relevant works with the categorization of the strategies to reverse ITME (Fig. 1 and Table 1).

Fig. 1: Nanosized drug delivery systems (NDDSs) modulating the immunosuppressive tumor microenvironment (ITME).
figure 1

Modulating the ITME based on NDDSs through promoting antigen release of tumor cells, maturation of dendritic cells (DCs), activation of cytotoxic T lymphocytes (CTLs), and tumor-killing effects of CTLs. DAMP damage-associated molecular pattern, TAA tumor-associated antigen, ICD immunogenetic cell death, TME tumor microenvironment, TAM tumor-associated macrophage, ROS reactive oxygen species, PD-1/PD-L1 programmed death 1/PD-1 ligand, IDO indoleamine 2,3-dioxygenase.

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Table 1 NDDS-based ITME-modulating strategies for improving antitumor immunotherapy.
Full size table

Combining ICD-inducing therapy with immunotherapy

ICD-inducing treatments provide an immune-activation environment for immunotherapy. Additionally, immunotherapy, including ICB and indoleamine 2,3-dioxygenase (IDO) inhibition, compensates for the upregulation of PD-L1 and IDO caused by IFN-γ, which is secreted by ICD-activated CTLs [40]. NDDSs can deliver targeted toxic ICD-inducing agents, including chemotherapeutic agents, radiotherapy sensitizers, and photosensitizers, to tumor sites, thus minimizing adverse effects and improving therapeutic outcomes [41, 42].

ICD induced by chemotherapy

The combination of chemotherapy and immunotherapy is an encouraging strategy because of the ICD-inducing ability of some chemotherapeutics. To improve the targeting and accessibility of ICD inducers to tumor cells, Li et al. fabricated a bioinspired lipoprotein system containing the legumain-sensitive melittin prodrug, the pH-sensitive phospholipid, and the nitroreductase-sensitive oxaliplatin [43]. After administration, the release of melittin by high-level legumain in tumors promoted the intratumoral permeation of the nanoplatform, and then, the size-enlargement of the nanoplatform after internalization as a response to acidity released oxaliplatin prodrug. Finally, the stimulation of oxaliplatin by nitroreductase and reductive environments induced ICD and elicited antitumor responses (Fig. 2a). Treatment with the nanoplatform increased the proportion of intratumoural CTLs and mature DCs by 1.76-fold and 3.57-fold, respectively, compared with free oxaliplatin treatment, indicating the importance of the delivery strategy. The combination of immune-activating treatment and ICB prolonged the survival of tumor-bearing mice compared with single therapy, demonstrating that preregulating the TME facilitated the effects of immunotherapy. A nanovesicle constructed by fusing artificial liposomes with tumor-derived nanovesicles was utilized for the targeted delivery of doxorubicin, which improved the immunogenicity of tumors and improved the therapeutic efficacy of ICB [44].

Fig. 2: NDDS-based ICD induction for improving immunotherapy.
figure 2

a Schematic illustration of the cancer-accessing tumor-activated size-enlargeable bioinspired lipoprotein system (TA-OBL) to boost antitumor immune responses and synergize with ICB-mediated immunotherapy. b Schematic illustration of the procedures for the evaluation of the activity of sHDL in inducing DC maturation and the proposed mechanism of action. c Treatment-induced extracellular release of ATP and HMGB1 from Hepa1-6 cells treated with different sHDLs. All of the experiments were performed in triplicate, and the data are presented as the mean ± SD (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001. d Schematic illustration of light-inducible nanocargoes (LINC) for improved drug delivery and chemoimmunotherapy by eliciting tumor immunogenicity and overcoming the immunosuppressive tumor microenvironment. e Tumor growth curves in 4T1 tumor-bearing mice after the indicated treatments (n = 6). Data are the mean ± SD. Statistical significance was calculated by one-way ANOVA. a Reproduced from Li et al. [43]. Copyright (2020) John Wiley & Sons. b, c Reproduced from Wang et al. [54]. Copyright (2019) American Chemical Society. d, e Reproduced from Feng et al. [59]. Copyright (2019) John Wiley & Sons.

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In addition to sequential delivery, codelivery of ICD inducers and immunotherapeutic agents by NDDSs is also a potential strategy. The tryptophan catabolic enzyme IDO inhibits immune effector cells and promotes immunosuppressive cells [45]. A nanoparticle containing oxaliplatin prodrugs and the IDO inhibitor NLG919 [46] and a biomimetic micelle/monocyte delivery system containing docetaxel, NLG919 and a PD-1/PD-L1 inhibitor [47] were constructed to enhance the efficiency of the drugs and amplify the synergetic effects. These NDDSs provide robust platforms for chemoimmunotherapy to mature DCs and powerfully activate CTLs.

ICD induced by phototherapy

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is capable of inducing ICD by generating reactive oxygen species (ROS) or local hyperthermia, respectively [41]. Given the high expression of matrix metalloproteinase 2 (MMP-2) in the TME, Wang and coworkers encapsulated an anti-PD-L1 antibody and a photosensitizer into MMP-2-responsive nanoparticles to precisely release drugs at the tumor site. Photosensitizer-mediated PDT under a near-infrared (NIR) laser sensitized the tumors to ICB [48]. Consequently, the tumor inhibition rate of mice treated with the nanoplatform and irradiation was 73.2%, which was only 39.8% of the free antibody-treated group. Similarly, a pH-sensitive nanoplatform loaded with a photosensitizer and a PD-L1 siRNA was constructed to overcome the immunological tolerance of tumors [49]. TME-activated nanoplatforms codelivering photosensitizers and IDO inhibitors [50, 51] or Toll-like receptor 3 (TLR3) agonists [

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Acknowledgements

National Natural Science Foundation of China (81871471, 31930066, 32130058, and 32171315), Natural Science Foundation of Shanghai (19ZR1479900), Science and Technology Commission of Shanghai Municipality (19431900800), International Partnership Program of CAS (153631KYSB20190013), Natural Science Foundation of Shandong (ZR2019ZD25), Special Research Assistant Project of CAS, China Postdoctoral Science Foundation (2020M681428), and Shanghai Postdoctoral Excellence Program (2020495) are gratefully acknowledged for financial support.

Author information

Author notes

  1. These authors contributed equally: Wen-lu Yan, Tian-qun Lang

Authors and Affiliations

  1. State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China

    Wen-lu Yan, Tian-qun Lang, Wen-hui Yuan, Qi Yin & Ya-** Li

  2. School of Pharmacy, University of Chinese Academy of Sciences, Bei**g, 100049, China

    Wen-lu Yan, Wen-hui Yuan, Qi Yin & Ya-** Li

  3. Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, 264000, China

    Tian-qun Lang & Qi Yin

  4. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China

    Ya-** Li

  5. School of Pharmacy, Yantai University, Yantai, 264005, China

    Ya-** Li

Authors
  1. Wen-lu Yan
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  2. Tian-qun Lang
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  3. Wen-hui Yuan
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  4. Qi Yin
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  5. Ya-** Li
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Corresponding authors

Correspondence to Qi Yin or Ya-** Li.

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Yan, Wl., Lang, Tq., Yuan, Wh. et al. Nanosized drug delivery systems modulate the immunosuppressive microenvironment to improve cancer immunotherapy. Acta Pharmacol Sin 43, 3045–3054 (2022). https://doi.org/10.1038/s41401-022-00976-6

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