The orally bioavailable GSPT1/2 degrader SJ6986 exhibits in vivo efficacy in acute lymphoblastic leukemia.

Advancing cure rates for high-risk acute lymphoblastic leukemia (ALL) has been limited by the lack of agents that effectively kill leukemic cells, sparing normal hematopoietic tissue. Molecular glues direct the ubiquitin ligase cellular machinery to target neosubstrates for protein degradation. We developed a novel cereblon modulator, SJ6986, that exhibits potent and selective degradation of GSPT1 and GSPT2 and cytotoxic activity against childhood cancer cell lines. Here, we report in vitro and in vivo testing of the activity of this agent in a panel of ALL cell lines and xenografts. SJ6986 exhibited similar cytotoxicity to the previously described GSPT1 degrader CC-90009 in a panel of leukemia cell lines in vitro, resulting in apoptosis and perturbation of cell cycle progression. SJ6986 was more effective than CC-90009 in suppressing leukemic cell growth in vivo, partly attributable to favorable pharmacokinetic properties, and did not significantly impair differentiation of human CD34+ cells ex vivo. Genome-wide CRISPR/Cas9 screening of ALL cell lines treated with SJ6986 confirmed that components of the CRL4CRBN complex, associated adaptors, regulators, and effectors were integral in mediating the action of SJ6986. SJ6986 is a potent, selective, orally bioavailable GSPT1/2 degrader that shows broad antileukemic activity and has potential for clinical development.

A phthalocyanine-based photosensitizer for effectively combating triple negative breast cancer with enhanced photodynamic anticancer activity and immune response.

Although photodynamic therapy (PDT) has attracted great interest, the photosensitizers in clinical had weak inhibition on metastasis and invasion of cancers. Additionally the immune response induced by PDT was insufficient to eradicate cancer. Herein, indoximod, an inhibitor of indoleamine 2,3-dioxygenase (IDO), is introduced to concatenate with zinc phthalocyanines (ZnPc) for effectively overcoming above inadequacy. Due to indoximod moiety, photosensitizer 1-MT-Pc can obtain enhanced intracellular uptake and high reactive oxygen species (ROS) generation. More impressively, 1-MT-Pc can achieve remarkable photocytotoxicity towards TNBC cells and negligible damage to normal cells. Meanwhile, 1-MT-Pc effectively inhibits metastasis and invasion of TNBC cells. Importantly, 1-MT-Pc exhibit elevated inhibitory effect on 4T1 tumor by enhanced PDT and immunotherapy.

Proximity interactome analysis of Lassa polymerase reveals eRF3a/GSPT1 as a druggable target for host-directed antivirals.

Completion of the Lassa virus (LASV) life cycle critically depends on the activities of the virally encoded, RNA-dependent RNA polymerase in replication and transcription of the viral RNA genome in the cytoplasm of infected cells. The contribution of cellular proteins to these processes remains unclear. Here, we applied proximity proteomics to define the interactome of LASV polymerase in cells under conditions that recreate LASV RNA synthesis. We engineered a LASV polymerase-biotin ligase (TurboID) fusion protein that retained polymerase activity and successfully biotinylated the proximal proteome, which allowed the identification of 42 high-confidence LASV polymerase interactors. We subsequently performed a small interfering RNA (siRNA) screen to identify those interactors that have functional roles in authentic LASV infection. As proof of principle, we characterized eukaryotic peptide chain release factor subunit 3a (eRF3a/GSPT1), which we found to be a proviral factor that physically associates with LASV polymerase. Targeted degradation of GSPT1 by a small-molecule drug candidate, CC-90009, resulted in strong inhibition of LASV infection in cultured cells. Our work demonstrates the feasibility of using proximity proteomics to illuminate and characterize yet-to-be-defined host-pathogen interactome, which can reveal new biology and uncover novel targets for the development of antivirals against highly pathogenic RNA viruses.

Covalent RGD-graphene-phthalocyanine nanocomposite for fluorescence imaging-guided dual active/passive tumor-targeted combinatorial phototherapy.

Poor tumor selectivity, low stability and quenched fluorescence are the main challenges to be overcome for nanomedicine, and are mainly caused by the dissociation of the nanostructure and aggregation of chromophores in the biological environment. Herein, covalently connected nanoparticles RGD-graphene-phthalocyanine (RGD-GO-SiPc) were constructed based on RGD peptide, silicon phthalocyanine (SiPc) and graphene oxide (GO) via a conjugation reaction for fluorescence imaging-guided cancer-targeted combinatorial phototherapy. The prepared RGD-GO-SiPc exhibited supreme biological stability, high-contrast fluorescence imaging, significantly enhanced NIR absorption, high photothermal conversion efficiency (25.6%), greatly improved cancer-targeting capability, and synergistic photodynamic (PDT) and photothermal therapy (PTT) efficacy along with low toxicity. Both in vitro and in vivo biological studies showed that RGD-GO-SiPc is a kind of promising multifunctional nanomedicine for fluorescence imaging-guided combined photothermal and photodynamic therapy with dual active/passive tumor-targeting properties.

The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus.

The main protease (Mpro or 3CLpro) of SARS-CoV-2 virus is a cysteine enzyme critical for viral replication and transcription, thus indicating a potential target for antiviral therapy. A recent repurposing effort has identified ebselen, a multifunctional drug candidate as an inhibitor of Mpro. Our docking of ebselen to the binding pocket of Mpro crystal structure suggests a noncovalent interaction for improvement of potency, antiviral activity and selectivity. To test this hypothesis, we designed and synthesized ebselen derivatives aimed at enhancing their non-covalent bonds within Mpro. The inhibition of Mpro by ebselen derivatives (0.3 µM) was screened in both HPLC and FRET assays. Nine ebselen derivatives (EBs) exhibited stronger inhibitory effect on Mpro with IC50 of 0.07-0.38 µM. Further evaluation of three derivatives showed that EB2-7 exhibited the most potent inhibition of SARS-CoV-2 viral replication with an IC50 value of 4.08 µM in HPAepiC cells, as compared to the prototype ebselen at 24.61 µM. Mechanistically, EB2-7 functions as a noncovalent Mpro inhibitor in LC-MS/MS assay. Taken together, our identification of ebselen derivatives with improved antiviral activity may lead to developmental potential for treatment of COVID-19 and SARS-CoV-2 infection.

Polycyclodextrin as a linker for nanomedicine fabrication and synergistic anticancer application.

Polycyclodextrin (denoted PCD) composed of cyclodextrin monomer units and 1,3-diethoxypropan-2-ol containing many hydroxyl groups with lone pairs of electrons, easily coordinated with transition metals with empty orbitals. The CD unit can also provide host-guest binding sites for functional molecules. This article utilizes this feature of PCD for the first time as a "linker" to combine transition metal nanomaterials with synergistic functional molecules. We synthesized PCD with 50% CD monomer by epichlorohydrin cross-linking method. Utilizing the coordination effect of the hydroxyl group in PCD and the iron ion in photothermal nanoparticles (PB-Yb), the PCD is coated on its surface; simultaneously, CD in PCD can form a host-guest complex with adamantane-modified zinc phthalocyanine (Pc) photosensitizer. Using PCD as a "linker", PB-Yb and Pc (denoted PYPP) were combined to improve the solubility of PB-Yb, reduce the aggregation degree of Pc to increase their activity, and achieve photothermal and photodynamic synergistic tumor therapy.

CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.

CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells.

A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982).

The HSP90 inhibitor Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy: an in vitro and in vivo approach.

Oncogenic client-proteins of the chaperone Heat shock protein 90 (HSP90) insure unlimited tumor growth and are involved in resistance to chemo- and radiotherapy. The HSP90 inhibitor Onalespib initiates the degradation of oncoproteins, and might also act as a radiosensitizer. The aim of this study was therefore to evaluate the efficacy of Onalespib in combination with external beam radiotherapy in an in vitro and in vivo approach. Onalespib downregulated client proteins, lead to increased apoptosis and caused DNA-double-strands. Monotherapy and combination with radiotherapy reduced colony formation, proliferation and migration assessed in radiosensitive HCT116 and radioresistant A431 cells. In vivo, a minimal treatment regimen for 3 consecutive days of Onalespib (3 × 10 mg/kg) doubled survival, whereas Onalespib with radiotherapy (3 × 2 Gy) caused a substantial delay in tumor growth and prolonged the survival by a factor of 3 compared to the HCT116 xenografted control group. Our results demonstrate that Onalespib exerts synergistic anti-cancer effects when combined with radiotherapy, most prominent in the radiosensitive cell models. We speculate that the depletion and downregulation of client proteins involved in signalling, migration and DNA repair mechanisms is the cause. Thus, individually, or in combination with radiotherapy Onalespib inhibits tumor growth and has the potential to improve radiotherapy outcomes, prolonging the overall survival of cancer patients.

Triple drugs co-delivered by a small gemcitabine-based carrier for pancreatic cancer immunochemotherapy.

Poor tumor penetration and highly immunosuppressive tumor microenvironment are two major factors that limit the therapeutic efficacy for the treatment of pancreatic ductal adenocarcinoma (PDA). In this work, a redox-responsive gemcitabine (GEM)-conjugated polymer, PGEM, was employed as a tumor penetrating nanocarrier to co-load an immunomodulating agent (NLG919, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) and a chemotherapeutic drug (paclitaxel (PTX)) for immunochemo combination therapy. The NLG919/PTX co-loaded micelles showed very small size of ~15 nm. In vivo tumor imaging study indicated that PGEM was much more effective than the relatively large-sized POEG-co-PVD nanoparticles (~160 nm) in deep tumor penetration and could reach the core of the pancreatic tumor. PTX formulated in the PGEM carrier showed improved tumor inhibition effect compared with PGEM alone. Incorporation of NLG919 in the formulation led to a more immunoactive tumor microenvironment with significantly decreased percentage of Treg cells, and increased percentages of CD4+ IFNγ+ T and CD8+ IFNγ+ T cells. PGEM micelles co-loaded with PTX and NLG919 showed the best anti-tumor activity in pancreatic (PANC02) as well as two other tumor models compared to PGEM micelles loaded with PTX or NLG919 alone, suggesting that codelivery of NLG919 and PTX via PGEM may represent an effective strategy for immunochemotherapy of PDA as well as other types of cancers. STATEMENT OF SIGNIFICANCE: In order to effectively accumulate and penetrate the PDA that is poorly vascularized and enriched with dense fibrotic stroma, the size of nanomedicine has to be well controlled. Here, we reported an immunochemotherapy regimen based on co-delivery of GEM, PTX and IDO1 inhibitor NLG919 through an ultra-small sized GEM-based nanocarrier (PGEM). We demonstrated that the PGEM carrier was effective in accumulating and penetrating into PDA tumors. Besides, PGEM co-loaded with PTX and NLG9 induced an improved anti-tumor immune response and was highly efficacious in inhibiting tumor growth as well as in prolonging the survival rate in PANC02 xenograft model. Our work represents a potential strategy for enhancing PDA tumor penetration and immunochemotherapy.

Engineering Stimuli-Activatable Boolean Logic Prodrug Nanoparticles for Combination Cancer Immunotherapy.

Prodrug nanoparticles that codeliver the immune modulators to the tumor site are highly recommendable for cancer immunotherapy yet remain challenging. However, effective stimuli-responsive strategies that exploit the endogenous hallmarks of the tumor have paved the way for cancer immunotherapy. For the first time, the development of the Boolean logic prodrug nanoparticles (BLPNs) for tumor-targeted codelivery of immune modulators (e.g., immune activator and immune inhibitor) and combination immunotherapy is reported herein. A library of stimuli-activatable BLPNs is fabricated yielding YES/AND logic outputs by adjusting the input combinations, including extracellular matrix metalloproteins 2/9 (MMP-2/9), intracellular acidity (pH = 5.0-6.0), and reduction (glutathione) in the tumor microenvironment. Tunable and selective control over BLPNs dissociation and prodrug activation is achieved by specifying the connectivity of orthogonal stimuli-labile spacers while exploiting the endogenous signals at the tumor sites. The tumor-specific distribution of the BLPNs and stimuli-activation of the immune modulators for highly efficient cancer immunotherapy are further demonstrated. The results reported in this study may open a new avenue for tumor-specific delivery of immune therapeutics and precise cancer immunotherapy.

Isoindoline scaffold-based dual inhibitors of HDAC6 and HSP90 suppressing the growth of lung cancer in vitro and in vivo.

This study reports the synthesis of a series of 2-aroylisoindoline hydroxamic acids employing N-benzyl, long alkyl chain and acrylamide units as diverse linkers. In-vitro studies led to the identification of N-benzyl linker-bearing compound (10) and long chain linker-containing compound (17) as dual selective HDAC6/HSP90 inhibitors. Compound 17 displays potent inhibition of HDAC6 isoform (IC50 = 4.3 nM) and HSP90a inhibition (IC50 = 46.8 nM) along with substantial cell growth inhibitory effects with GI50 = 0.76 µM (lung A549) and GI50 = 0.52 µM (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI50 = 0.37 µM) and lung H1975 cell lines (GI50 = 0.13 µM) mediated through selective HDAC6 inhibition (IC50 = 33.3 nM) and HSP90 inhibition (IC50 = 66 nM). In addition, compound 17 also modulated the expression of signatory biomarkers associated with HDAC6 and HSP90 inhibition. In the in vivo efficacy evaluation in human H1975 xenografts, 17 induced slightly remarkable suppression of tumor growth both in monotherapy as well as the combination therapy with afatinib (20 mg/kg). Moreover, compound 17 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner suggesting that dual inhibition of HDAC6 and HSP90 can modulate immunosuppressive ability of tumor area.

Role of androgen receptor splice variants, their clinical relevance and treatment options.

PURPOSE: In this review, we summarize the importance of AR variants with a particular focus on clinically relevant members of this family. METHODS: A non-systematic literature review was performed based on Medline and PubMed. RESULTS: Endocrine therapy represents the central paradigm for the management of prostate cancer. Eventually, in response to androgen ablation therapy, several resistance mechanisms against the endocrine therapy might develop that can circumvent the therapy approaches. One specific resistance mechanism that has gained increasing attention is the generation of alternatively spliced variants of the androgen receptor, with AR-V7 being the most prominent. More broadly, AR-V7 is one member of a group of alternatively spliced AR variants that share a common feature, the missing ligand-binding domain. These ΔLBD androgen receptor variants have shown the capability to induce androgen receptor-mediated gene transcription even under conditions of androgen deprivation and to drive cancer progression. CONCLUSION: The methods used for detecting AR-Vs, at least on the mRNA level, are well-advanced and harbor the potential to be introduced into clinical diagnostics. It is important to note, that the testing, especially of AR-V7 has its limitations in predicting treatment response. More promising is the great number of active clinical trials aimed at reducing the AR-Vs, and using this to re-sensitize CRPC towards endocrine treatment might provide additional treatment options for CRPC patients in the future.

Synthesis and biological evaluation of new chloro/acetoxy substituted isoindole analogues as new tyrosine kinase inhibitors.

We have developed a versatile synthetic approach for the synthesis of new isoindole derivatives via the cleavage of ethers from tricyclic imide skeleton compounds. An exo-cycloadduct prepared from the Diels-Alder reaction of furan and maleic anhydride furnished imide derivatives. The epoxide ring was opened with Ac2O or Ac2O/AcCl in the presence of a catalytic amount of H2SO4 in order to yield new isoindole derivatives 8a-d and 9a-d. The anticancer activity of these compounds was evaluated against the HeLa cell lines. The synthesized compounds showed inhibitory effects on the viability of HeLa cells and the degree of cytotoxicity was increased with the level of bigger branched isoindole derivatives. To better understand the acting mechanism of these molecules, western blot analysis was performed with using mTOR and its downstream substrates. In addition, human mTOR and ribozomal S6 kinase ß1 (RS6Kß1) have been investigated with molecular modelling studies as possible targets for compound series 8 and 9.

The HSP90 inhibitor onalespib potentiates 177Lu­DOTATATE therapy in neuroendocrine tumor cells.

177Lu­DOTATATE was recently approved for the treatment of somatostatin receptor (SSTR)­positive neuroendocrine tumors (NETs). However, despite impressive response rates, complete responses are rare. Heat shock protein 90 (HSP90) inhibitors have been suggested as suitable therapeutic agents for NETs, as well as a potential radiosensitizers. Consequently, the aim of this study was to investigate whether the HSP90­inhibitor onalespib could reduce NET cell growth and act as a radiosensitizer when used in combination with 177Lu­DOTATATE. The NET cell lines BON, NCI­H727 and NCI­H460, were first characterized with regards to 177Lu­DOTATATE uptake and sensitivity to onalespib treatment in monolayer cell assays. The growth inhibitory effects of the monotherapies and combination treatments were then examined in three­dimensional multicellular tumor spheroids. Lastly, the molecular effects of the treatments were assessed. 177Lu­DOTATATE uptake was observed in the BON and NCI­H727 cells, while the NCI­H460 cells exhibited no detectable uptake. Accordingly, 177Lu­DOTATATE reduced the growth of BON and NCI­H727 spheroids, while no effect was observed in the NCI­H460 spheroids. Onalespib reduced cell viability and spheroid growth in all three cell lines. Furthermore, the combination of onalespib and 177Lu­DOTATATE exerted synergistic therapeutic effects on the BON and NCI­H727 spheroids. Western blot analysis of BON spheroids revealed the downregulation of epidermal growth factor receptor (EGFR) and the upregulation of γ H2A histone family member X (γH2AX) following combined treatment with onalespib and 177Lu­DOTATATE. Moreover, flow cytometric analyses revealed a two­fold increase in caspase 3/7 activity in the combination group. In conclusion, the findings of this study demonstrate that onalespib exerts antitumorigenic effects on NET cells and may thus be a feasible treatment option for NETs. Furthermore, onalespib was able to synergistically potentiate 177Lu­DOTATATE treatment in a SSTR­specific manner. The radiosensitizing mechanisms of onalespib involved the downregulation of EGFR expression and the induction of apoptosis. Consequently, the combination of onalespib and 177Lu­DOTATATE may prove to be a promising strategy with which to improve therapeutic responses in patients with NETs. Further studies investigating this strategy in vivo regarding the therapeutic effects and potential toxicities are warranted to expand these promising findings.

Enhanced cancer therapy through synergetic photodynamic/immune checkpoint blockade mediated by a liposomal conjugate comprised of porphyrin and IDO inhibitor.

Cancer metastases is still a hurdle for good prognosis and live quality of breast cancer patients. Treatment strategies that can inhibit metastatic cancer while treating primary cancer are needed to improve the therapeutic effect of breast cancer. Methods: In this study, a dual functional drug conjugate comprised of protoporphyrin IX and NLG919, a potent indoleamine-2,3-dioxygenase (IDO) inhibitor, is designed to combine photodynamic therapy and immune checkpoint blockade to achieve both primary tumor and distant metastases inhibition. Liposomal delivery is applied to improve the biocompatibility and tumor accumulation of the drug conjugate (PpIX-NLG@Lipo). A series of in vitro and in vivo experiments were carried out to examine the PDT effect and IDO inhibition activity of PpIX-NLG@Lipo, and subsequently evaluate its anti-tumor capability in the bilateral 4T1 tumor-bearing mice. Results: The in vitro and in vivo experiments demonstrated that PpIX-NLG@Lipo possess strong ability of ROS generation to damage cancer cells directly through PDT. Meanwhile, PpIX-NLG@ Lipo can induce immunogenic cell death to elicit the host immune system. Furthermore, PpIX-NLG@Lipo interferes the activity of IDO, which can amplify PDT-induced immune responses, leading to an increasing amount of CD8+ T lymphocytes infiltrated into tumor site, finally achieve both primary and distant tumor inhibition. Conclusion: This work presents a novel conjugate approach to synergize photodynamic therapy and IDO blockade for enhanced cancer therapy through simultaneously inhibiting both primary and distant metastatic tumor.

NLG919/cyclodextrin complexation and anti-cancer therapeutic benefit as a potential immunotherapy in combination with paclitaxel.

NLG919 is an effective small molecule inhibitor of indoleamine 2, 3-dioxygenase-1 (IDO-1) in anti-tumour immunotherapy, but the poor aqueous solubility limits its application for effective intravenous dosing. In this study a cyclodextrin (CD) complexation strategy has been systematically evaluated to achieve a simple and feasible method to prepare an NLG919 injectable formulation. From a series of CDs, HP-ß-CD proved to be the most conducive for NLG919 solubilization (approx 800-fold increase). Characterization studies using DSC, 1H NMR, XRPD and molecular simulation demonstrated that the NLG919/HP-ß-CD loading mechanism involved an increasing pH-dependent binding affinity. Importantly cell-based studies in vitro and anti-tumour activity in vivo demonstrated that the pharmacological activity of NLG919 as an IDO-1 inhibitor was not influenced by HP-ß-CD complexation. Furthermore, the combination of NLG919/HP-ß-CD with paclitaxel (PTX) significantly improved anti-tumour chemotherapy compared to PTX alone. In summary, NLG919/HP-ß-CD is shown to highly enhance the aqueous solubility of NLG919 with activity unaffected, greatly facilitating the intravenous use of this small molecule immunotherapeutic to improve the efficacy of PTX.

Hypoxia alleviation-triggered enhanced photodynamic therapy in combination with IDO inhibitor for preferable cancer therapy.

Photodynamic therapy (PDT) has attracted growing attention in the field of cancer therapy due to its non-invasive intervention and initiation of antitumor immune responses by use of non-toxic photosensitizers (PS) and topical light irradiation. However, inherent hypoxia and immunosuppression mediated by checkpoints in tumors severally impair the efficacy of PDT and PDT-induced immunity. Herein, a multi-functional nanoplatform is rationally constructed by fluorinated polymer nanoparticle saturated with oxygen in advance, which simultaneously encapsulated PS (Ce6) and an indoleamine 2,3-dioxygenase (IDO) inhibitor (NLG919). In particular, the tumor hypoxic microenvironment is obviously relieved and much more reactive oxygen species (ROS) is generated by fluorinated nanoparticle compared with alkylated polymer nanoparticle as a control in vitro and in vivo, this is mainly because the fluorinated polymers are endowed with high oxygen carrying capacity which also contributed to the relief of hypoxia. Meanwhile, compared to PDT alone, the co-encapsulation of IDO inhibitor and PS can further greatly enhance efficacy for inhibiting the growth of primary and abscopal tumors via enhanced T cell infiltration. This study can provide a convenient and practical strategy for enhancing the therapeutic effect of PDT and relieving immune suppression, in turn affording clinical benefits for cancer treatment.