Search

In recent years, immunotherapy has produced many unexpected breakthroughs in oncological therapy; however, it still has many deficiencies. For example, the number of patients who are unresponsive to anti-programmed death-ligand 1 (PD-L1), anti-cytotoxic T-like antigen-4 (CTLA4), and anti-programmed death-1 (PD1) therapies cannot be ignored, and the search for an undiscovered immunosuppressive pathway is imminent. Five decades ago, researchers found that activation of the adenosinergic pathway was negatively correlated with prognosis in many cancers. This review describes the entire process of the adenosinergic pathway in the tumor microenvironment and the mechanism of immunosuppression, which promotes tumor metastasis and drug resistance. Additionally, the review explores factors that regulate this pathway, including signaling factors secreted by the tumor microenvironment and certain anti-tumor drugs. Additionally, the combination of adenosinergic pathway inhibitors with chemotherapy, checkpoint blockade therapy, and immune cell-based therapy is summarized. Finally, certain issues regarding treatment via inhibition of this pathway and the use of targeted nanoparticles to reduce adverse reactions in patients are put forward in this review. Graphical Abstract The inhibitors of adenosinergic pathway loaded nanoparticles enter tumor tissue through EPR effect, and inhibit adenosinergic pathway to enhance or restore the effect of immune checkpoint blockade therapy, chemotherapies and immune cell-based therapy. Note: EPR means enhanced penetration and retention, × means blockade.

Objectives Hypericin is a polycyclic aromatic naphthodianthrone that occurs naturally. It is also an active ingredient in some species of the genus Hypericum. Emerging evidence suggests that hypericin has attracted great attention as a potential anticancer drug and exhibits remarkable antiproliferative effect upon irradiation on various tumour cells. This paper aims to summarise the anticancer effect and molecular mechanisms modulated by hypericin-medicated photodynamic therapy and its potential role in the cancer treatment. Key findings Hypericin-medicated photodynamic therapy could inhibit the proliferation of various tumour cells including bladder, colon, breast, cervical, glioma, leukaemia, hepatic, melanoma, lymphoma and lung cancers. The effect is primarily mediated by p38 mitogen-activated protein kinase (MAPK), JNK, PI3K, CCAAT-enhancer-binding protein homologous protein (CHOP)/TRIB3/Akt/mTOR, TRAIL/TRAIL-receptor, c-Met and Ephrin-Eph, the mitochondria and extrinsic signalling pathways. Furthermore, hypericin-medicated photodynamic therapy in conjunction with chemotherapeutic agents or targeted therapies is more effective in inhibiting the growth of tumour cells. Summary During the past few decades, the anticancer properties of photoactivated hypericin have been extensively investigated. Hypericin-medicated photodynamic therapy can modulate a variety of proteins and genes and exhibit a great potential to be used as a therapeutic agent for various types of cancer.

Immunotherapy has exhibited enormous practice in the treatment of melanoma because of the intrinsic properties of tumor. Tumor can downmodulate immune function via multiple mechanisms such as immune checkpoint pathways. The PD-L1 monoclonal antibodies that block the PD1/PD-L1 pathway, which induced tumor cells to evade an immune attack, can delay tumor growth efficiently with inevitable disadvantages such as low selectivity and systemic toxicity. Nanomedicine is clearly an approach that holds tremendous potential for addressing the shortcomings and assisting delivery of drugs with proper biodistribution. Herein, we developed a smart nanoplatform with precisely active targeting liposome co-loaded chemotherapy and immunotherapy drugs for synergistic antitumor effects while decreasing systemic toxicity. Immunoliposomes have stable pharmaceutical properties and show a significant antitumor effect in vivo and in vitro. Cellular uptake in vitro and biodistribution in vivo demonstrated that immunoliposomes could be delivered and accumulated more in tumor tissues. These immunoliposomes exhibited effective tumor inhibition and prolonged survival time due to activation of tumor-specific CD8+ T cell and highly selective tumor killing. In addition, safety evaluation of liposomes also demonstrated their increased tumor accumulation and decreased systemic toxicity. Hence, this smart pH-sensitive nanoplatform has promising potential for clinical applications and possibly provides a well-controlled design for combination of chemotherapy with various immunotherapies for further exploration.

In this study, novel prodrug-modified cationic liposome nanocomplexes (Combo NCs) were reported for gemcitabine (GEM) and docetaxel (DTX) co-delivery. This nanoplatform exhibited multiple favorable characteristics, such as a 'green' fabrication with a one-step chemical reaction, appropriate size (∼200nm) and distribution (PDI0.2), low zeta potential (-31.1mv), high drug-loading efficiency (9.3% GEM plus 3.1% DTX, wt%) and pH and enzymatic dual-stimulus-responsive release properties. Immunofluorescence and cellular uptake studies showed that Combo NCs efficiently targeted overexpressed CD44 in MDA-MB-231 carcinoma. In vitro studies revealed that Combo NCs played a critical role in the synergistic induction of cytotoxicity, apoptosis and inhibition of wound healing. Combo NCs were confirmed to exhibit great potency for increasing S phase arrest and remodeling the CDA and dCK balance by decreasing the mRNA expression of CDA down to 0.09-fold and increasing the mRNA expression of dCK by 1.36-fold, remarkably increasing the dCK/CDA ratio to 15.3-fold compared with the blank control. The biodistribution results obtained in vivo revealed an effective accumulation in tumor foci. All of these advantages of Combo NCs contributed to their remarkable anti-tumor efficacy without systemic toxicity as well as their apoptosis-enhancing and anti-proliferative capacities, as determined by TUNEL and Ki67 immunohistochemistry in vivo. Consequently, such a rationally contemplated co-delivery system demonstrated the promising potential of clinical applications for triple-negative breast cancer therapy.The Combo NCs were innovatively applied for co-delivery of hydrophilic GEM and hydrophobic DTX. The ester bond linking and shielding effect of HA-GEM made the carriers achieve synchronous release properties, which was determined in in vitro release study. Due to the HA modification, the vectors own great potency for positive targeting to CD44 overexpressed triple-negative breast cancer cells MDA-MB-231. Cytotoxicity and apoptosis studies confirmed the targeting effect and synergism between two drugs. Interestingly, we found in cell cycle study, drug combinations (free combination or Combo NCs) didn't show a rise in G2M phase, which was significantly higher when treated DTX alone. We further discovered the role of DTX in combinations may involve in modulating GEM associated enzymes thus enhancing the efficacy of GEM. Consequently, this nanoplatform provided a novel solution for achieving targeted co-delivery and potentiating effect in cancer therapy.

Cancer immunotherapy has shown remarkable progress in recent years. Nanocarriers, such as liposomes, have favorable advantages with the potential to further improve cancer immunotherapy and even stronger immune responses by improving cell type-specific delivery and enhancing drug efficacy. Liposomes can offer solutions to common problems faced by several cancer immunotherapies, including the following: (1) Vaccination: Liposomes can improve the delivery of antigens and other stimulatory molecules to antigen-presenting cells or T cells; (2) Tumor normalization: Liposomes can deliver drugs selectively to the tumor microenvironment to overcome the immune-suppressive state; (3) Rewiring of tumor signaling: Liposomes can be used for the delivery of specific drugs to specific cell types to correct or modulate pathways to facilitate better anti-tumor immune responses; (4) Combinational therapy: Liposomes are ideal vehicles for the simultaneous delivery of drugs to be combined with other therapies, including chemotherapy, radiotherapy, and phototherapy. In this review, different liposomal systems specifically developed for immunomodulation in cancer are summarized and discussed.

Future cancer therapy will depend on combination therapy with multiple drugs to achieve maximum effects and minimum toxicity. Due to the complexity and significance of the tumor microenvironment (TME), it is vital to elucidate this complicated environment when designing a co-delivery system. There are numerous potent target sites in the TME to facilitate simultaneous and selective delivery. Currently, nanocarriers are used frequently in co-delivery systems for multiple antitumor treatments. Nanocarriers can efficiently deliver drugs and achieve synergistic effects, but the potent barriers in the TME and their inherent limitations have restricted their use. It is crucial to design an effected co-delivery system associated with the TME to achieve better anti-tumor activity, which we define as a "stereoscopic response." Although there are many obstacles in this field, the combination of simultaneous response in the TME with drug activity may present a promising strategy to achieve innovative, safe, and effective treatment.

As current tumor chemotherapy faces many challenges, it is important to develop drug delivery systems with increased tumor-targeting ability, enhanced therapeutic effects and reduced side effects. In this study, a pH-sensitive liposome was constructed containing CHEMS-anchored PEG2000 for extended circulation and NGR peptide as the targeting moiety. The NGR-modified docetaxel-loaded pH-sensitive extended-circulation liposomes (DTX/NGR-PLL) prepared possess suitable physiochemical properties, including particle size of approximately 200nm, drug encapsulation efficiency of approximately 70%, and pH-sensitive drug release properties. Experiments performed in vitro and in vivo on human fibrosarcoma cells (HT-1080) and human breast adenocarcinoma cells (MCF-7) verified the specific targeting ability and enhanced antitumor activity to HT-1080 cells. The results of intravenous administration demonstrated that NGR-modified liposomes can significantly and safely accumulate in tumor tissue in xenografted nude mice. In conclusion, the liposomes constructed hold promise as a safe and efficient drug delivery system for specific tumor treatment.