Artificial Engineered Natural Killer Cells Combined with Antiheat Endurance as a Powerful Strategy for Enhancing Photothermal‐Immunotherapy Efficiency of Solid Tumors

Although photothermal therapy (PTT) is preclinically applied in solid tumor treatment, incomplete tumor removal of PTT and heat endurance of tumor cells induces significant tumor relapse after treatment, therefore lowering the therapeutic efficiency of PTT. Herein, a programmable therapeutic strategy that integrates photothermal therapeutic agents (PTAs), DNAzymes, and artificial engineered natural killer (A‐NK) cells for immunotherapy of hepatocellular carcinoma (HCC) is designed. The novel PTAs, termed as Mn‐CONASHs, with 2D structure are synthesized by the coordination of tetrahydroxyanthraquinone and Mn²⁺ ions. By further adsorbing polyetherimide/DNAzymes on the surface, the DNAzymes@Mn‐CONASHs exhibit excellent light‐to‐heat conversion ability, tumor microenvironment enhanced T₁‐MRI guiding ability, and antiheat endurance ability. Furthermore, the artificial engineered NK cells with HCC specific targeting TLS11a‐aptamer decoration are constructed for specifically eliminating any possible residual tumor cells after PTT, to systematically enhance the therapeutic efficacy of PTT and avoid tumor relapse. Taken together, the potential of A‐NK cells combined with antiheat endurance as a powerful strategy for immuno‐enhancing photothermal therapy efficiency of solid tumors is highlighted, and the current strategy might provide promising prospects for cancer therapy.     

Transforming Weakness into Strength: Photothermal‐Therapy‐Induced Inflammation Enhanced Cytopharmaceutical Chemotherapy as a Combination Anticancer Treatment

A new synergistic treatment that combines photothermal therapy (PTT) and inflammation‐mediated active targeting (IMAT) chemotherapy based on cytopharmaceuticals is developed. During PTT, the photothermal tumor ablation is accompanied by an inflammatory effect and upregulation of inflammatory factors at the tumor site, which may accelerate tumor regeneration. Moreover, PTT‐induced inflammation can also recruit neutrophils (NEs) to the tumor site. To convert the disadvantages of PTT‐induced inflammation into strengths, NEs are investigated as cytopharmaceuticals for IMAT chemotherapy to further inhibit the tumor recurrence after PTT due to the chemotaxis of NEs to the inflammatory sites. In this study, PEGylated gold nanorods (PEG‐GNRs) are explored as the photothermal agent and paclitaxel‐loaded cytopharmaceuticals of NEs as the IMAT chemotherapeutic agent. PTT is conducted at 72 h postinjection of PEG‐GNRs, followed by cytopharmaceuticals for IMAT chemotherapy. It is demonstrated that the cytopharmaceuticals effectively accumulate in the tumor sites after PTT, which leads to a significant enhancement of antitumor efficacy and a reduction in systemic toxicity. These studies suggest that PTT‐induced inflammation further enhances the chemotherapy of cytopharmaceuticals, and the combination of PTT and IMAT chemotherapy may be a promising synergistic strategy for targeted cancer therapy.     

Layered MoS2 Hollow Spheres for Highly‐Efficient Photothermal Therapy of Rabbit Liver Orthotopic Transplantation Tumors

Combining photothermal therapy (PTT) with clinical technology to kill cancer via overcoming the low tumor targeting and poor therapy efficiency has great potential in basic and clinical researches. A brand‐new MoS₂ nanostructure is designed and fabricated, i.e., layered MoS₂ hollow spheres (LMHSs) with strong absorption in near‐infrared region (NIR) and high photothermal conversion efficiency via a simple and fast chemical aerosol flow method. Owing to curving layered hollow spherical structure, the as‐prepared LMHSs exhibit unique electronic properties comparing with MoS₂ nanosheets. In vitro and in vivo studies demonstrate their high photothermal ablation of cell and tumor elimination rate by single NIR light irradiation. Systematic acute toxicity study indicates that these LMHSs have negligible toxic effects to normal tissues and blood. Remarkably, minimally invasive interventional techniques are introduced to improve tumor targeting of PTT agents for the first time. To explore PTT efficiency on orthotopic transplantation tumors, New Zealand white rabbits with VX₂ tumor in liver are used as animal models. The effective elimination of tumors is successfully realized by PTT under the guidance of digital subtraction angiography, computed tomography, and thermal imaging, which provides a new way for tumor‐targeting delivery and cancer theranostic application.     

A Hollow‐Structured CuS@Cu2S@Au Nanohybrid: Synergistically Enhanced Photothermal Efficiency and Photoswitchable Targeting Effect for Cancer Theranostics

It is of great importance in drug delivery to fabricate multifunctional nanocarriers with intelligent targeting properties, for cancer diagnosis and therapy. Herein, hollow‐structured CuS@Cu₂S@Au nanoshell/satellite nanoparticles are designed and synthesized for enhanced photothermal therapy and photoswitchable targeting theranostics. The remarkably improved photothermal conversion efficiency of CuS@Cu₂S@Au under 808 nm near‐infrared (NIR) laser irradiation can be explained by the reduced bandgap and more circuit paths for electron transitions for CuS and Cu₂S modified with Au nanoparticles, as calculated by the Vienna ab initio simulation package, based on density functional theory. By modification of thermal‐isomerization RGD targeting molecules and thermally sensitive copolymer on the surface of nanoparticles, the transition of the shielded/unshielded mode of RGD (Arg‐Gly‐Asp) targeting molecules and shrinking of the thermally sensitive polymer by NIR photoactivation can realize a photoswitchable targeting effect. After loading an anticancer drug doxorubicin in the cavity of CuS@Cu₂S@Au, the antitumor therapy efficacy is greatly enhanced by combining chemo‐ and photothermal therapy. The reported nanohybrid can also act as a photoacoustic imaging agent and an NIR thermal imaging agent for real‐time imaging, which provides a versatile platform for multifunctional theranostics and stimuli‐responsive targeted cancer therapy.     

Photosensitizer‐Conjugated Albumin−Polypyrrole Nanoparticles for Imaging‐Guided In Vivo Photodynamic/Photothermal Therapy

Conjugated polymers with strong absorbance in the near‐infrared (NIR) region have been widely explored as photothermal therapy agents due to their excellent photostability and high photothermal conversion efficiency. Herein, polypyrrole (PPy) nanoparticles are fabricated by using bovine serum albumin (BSA) as the stabilizing agent, which if preconjugated with photosensitizer chlorin e6 (Ce6) could offer additional functionalities in both imaging and therapy. The obtained PPy@BSA‐Ce6 nanoparticles exhibit little dark toxicity to cells, and are able to trigger both photodynamic therapy (PDT) and photothermal therapy (PTT). As a fluorescent molecule that in the meantime could form chelate complex with Gd³⁺, Ce6 in PPy@BSA‐Ce6 nanoparticles after being labeled with Gd³⁺ enables dual‐modal fluorescence and magnetic resonance (MR) imaging, which illustrate strong tumor uptake of those nanoparticles after intravenous injection into tumor‐bearing mice. In vivo combined PDT and PTT treatment is then carried out after systemic administration of PPy@BSA‐Ce6, achieving a remarkably improved synergistic therapeutic effect compared to PDT or PTT alone. Hence, a rather simple one‐step approach to fabricate multifunctional nanoparticles based on conjugated polymers, which appear to be promising in cancer imaging and combination therapy, is presented.     

Somatostatin Receptor‐Mediated Tumor‐Targeting Nanocarriers Based on Octreotide‐PEG Conjugated Nanographene Oxide for Combined Chemo and Photothermal Therapy

Nano‐sized in vivo active targeting drug delivery systems have been developed to a high anti‐tumor efficacy strategy against certain cancer‐cells‐specific. Graphene based nanocarriers with unique physical and chemical properties have shown significant potentials in this aspect. Here, octreotide (OCT), an efficient biotarget molecule, is conjugated to PEGylated nanographene oxide (NGO) drug carriers for the first time. The obtained NGO‐PEG‐OCT complex shows low toxicity and excellent stability in vivo and is able to achieve somatostatin receptor‐mediated tumor‐specific targeting delivery. Owing to the high loading efficiency and accurate targeting delivery of anti‐cancer drug doxorubicin (DOX), our DOX loaded NGO‐PEG‐OCT complex offers a remarkably improved cancer‐cell‐specific cellular uptake, chemo‐cytotoxicity, and decreased systemic toxicity compared to free DOX or NGO‐PEG. More importantly, due to its strong near‐infrared absorption, the NGO‐PEG‐OCT complex further enhances efficient photothermal ablation of tumors, delivering combined chemo and photothermal therapeutic effect against cancer cells.     

Boron Dipyrromethene Nano‐Photosensitizers for Anticancer Phototherapies

As traditional phototherapy agents, boron dipyrromethene (BODIPY) photosensitizers have attracted increasing attention due to their high molar extinction coefficients, high phototherapy efficacy, and excellent photostability. After being formed into nanostructures, BODIPY‐containing nano‐photosensitizers show enhanced water solubility and biocompatibility as well as efficient tumor accumulation compared to BODIPY molecules. Hence, BODIPY nano‐photosensitizers demonstrate a promising potential for fighting cancer. This review contains three sections, classifying photodynamic therapy (PDT), photothermal therapy (PTT), and the combination of PDT and PTT based on BODIPY nano‐photosensitizers. It summarizes various BODIPY nano‐photosensitizers, which are prepared via different approaches including molecular precipitation, supramolecular interactions, and polymer encapsulation. In each section, the design strategies and working principles of these BODIPY nano‐photosensitizers are highlighted. In addition, the detailed in vitro and in vivo applications of these recently developed nano‐photosensitizers are discussed together with future challenges in this field, highlighting the potential of these promising nanoagents for new tumor phototherapies.     

Multifunctional Conjugated Polymer Nanoparticles for Image‐Guided Photodynamic and Photothermal Therapy

A multifunctional theranostic platform based on conjugated polymer nanoparticles (CPNs) with tumor targeting, fluorescence detection, photodynamic therapy (PDT), and photothermal therapy (PTT) is developed for effective cancer imaging and therapy. Two conjugated polymers, poly[9,9‐bis(2‐(2‐(2‐methoxyethoxy)ethoxy)‐ethyl)fluorenyldivinylene]‐alt‐4,7‐(2,1,3‐benzothiadiazole) with bright red emission and photosensitizing ability and poly[(4,4,9,9‐tetrakis(4‐(octyloxy)phenyl)‐4,9‐dihydro‐s‐indacenol‐dithiophene‐2,7‐diyl)‐alt‐co‐4,9‐bis(thiophen‐2‐yl)‐6,7‐bis(4‐(hexyloxy)phenyl)‐thiadiazolo‐quinoxaline] with strong near‐infrared absorption and excellent photothermal conversion ability are co‐loaded into one single CPN via encapsulation approach using lipid‐polyethylene glycol as the matrix. The obtained co‐loaded CPNs show sizes of around 30 nm with a high singlet oxygen quantum yield of 60.4% and an effective photothermal conversion efficiency of 47.6%. The CPN surface is further decorated with anti‐HER2 affibody, which bestows the resultant anti‐HER2‐CPNs superior selectivity toward tumor cells with HER2 overexpression both in vitro and in vivo. Under light irradiation, the PDT and PTT show synergistic therapeutic efficacy, which provides new opportunities for the development of multifunctional biocompatible organic materials in cancer therapy.     

Fast‐Clearable Nanocarriers Conducting Chemo/Photothermal Combination Therapy to Inhibit Recurrence of Malignant Tumors

Inhomogeneous heating by photothermal therapy (PTT) during cancer treatment often results in the recurrence of tumors. Thus, integrating PTT with chemotherapy (CHT) may provide a complementary treatment for enhanced therapeutic efficiency. Herein, this study develops a hollow structured polymer–silica nanohybrid (HPSN) as a nanocarrier to simultaneously deliver the anticancer drug paclitaxel and photothermal agent palladium phthalocyanine to tumors through enhanced permeation and the retention effect. A combinational CHT/PTT therapy on mice bearing aggressive tumor grafts is conducted. The highly malignant tumor model, which recurs after sole treatment of PTT, can be eradicated by the combined CHT/PTT treatment. In addition, most of the off‐targeted HPSN nanocarriers can be excreted through a hepatobiliary pathway in about 10 d. Serology results show that the fast‐clearable HPSN can significantly reduce the side effect of the loaded paclitaxel drug. The present work provides an alternative approach for combinational cancer treatment with high therapeutic efficiency.     

First Demonstration of Gold Nanorods‐Mediated Photodynamic Therapeutic Destruction of Tumors via Near Infra‐Red Light Activation

Previously, a large volume of papers reports that gold nanorods (Au NRs) are able to effectively kill cancer cells upon high laser doses (usually 808 nm, 1–48 W/cm²) irradiation, leading to hyperthermia‐induced destruction of cancer cells, i.e, photothermal therapy (PTT) effects. Combination of Au NRs‐mediated PTT and organic photosensitizers‐mediated photodynamic therapy (PDT) were also reported to achieve synergistic PTT and PDT effects on killing cancer cells. Herein, we demonstrate for the first time that Au NRs alone can sensitize formation of singlet oxygen (¹O₂) and exert dramatic PDT effects on complete destrcution of tumors in mice under very low LED/laser doses of single photon NIR (915 nm, <130 mW/cm²) light excitation. By changing the NIR light excitation wavelengths, Au NRs‐mediated phototherapeutic effects can be switched from PDT to PTT or combination of both. Both PDT and PTT effects were confirmed by measurements of reactive oxygen species (ROS) and heat shock protein (HSP 70), singlet oxygen sensor green (SOSG) sensing, and sodium azide quenching in cellular experiments. In vivo mice experiments further show that the PDT effect via irradiation of Au NRs by 915 nm can destruct the B16F0 melanoma tumor in mice far more effectively than doxorubicin (a clinically used anti‐cancer drug) as well as the PTT effect (via irradiation of Au NRs by 780 nm light). In addition, we show that Au NRs can emit single photon‐induced fluorescence to illustrate their in vivo locations/distribution.     

Gold nanorod-photosensitizer conjugate with extracellular pH-driven tumor targeting ability for photothermal/photodynamic therapy

Chlorin e6-pHLIPss-AuNRs, a gold nanorod-photosensitizer conjugate containing a pH （low） insertion peptide （pHLIP） with a disulfide bond which imparts extracellular pH （pHe）-driven tumor targeting ability, has been successfully developed for bimodal photodynamic and photothermal therapy. In this bimodal therapy, chlorin e6 （Ce6）, a second-generation photosensitizer （PS）, is used for photodynamic therapy （PDT）. Gold nanorods （AuNRs） are used as a hyperthermia agent for photothermal therapy （PTT） and also as a nanocarrier and quencher of Ce6. pHLIPss is designed as a pile-driven targeting probe to enhance accumulation of Ce6 and AuNRs in cancer cells at low pH. In Ce6- pHLIPss-AuNRs, Ce6 is close to and quenched by AuNRs, causing little PDT effect. When exposed to normal physiological pH 7.4, Ce6-pHLIPs~-AuNRs loosely associate with the cell membrane. However, once exposed to acidic pH 6.2, pHLIP actively inserts into the cell membrane, and the conjugates are translocated into cells. When this occurs, Ce6 separates from the AuNRs as a result of disulfide bond cleavage caused by intracellular glutathione （GSH）, and singlet oxygen is produced for PDT upon light irradiation. In addition, as individual PTT agent, AuNRs can enhance the accumulation of PSs in the tumor by the enhanced permeation and retention （EPR） effect. Therefore, as indicated by our data, when exposed to acidic pH, Ce6-pHLIPss-AuNRs can achieve synergistic PTT/PDT bimodality for cancer treatment.     

Enhanced Photothermal Therapy through the In Situ Activation of a Temperature and Redox Dual‐Sensitive Nanoreservoir of Triptolide

Photothermal therapy (PTT) has attracted tremendous attention due to its noninvasiveness and localized treatment advantages. However, heat shock proteins (HSPs) associated self‐preservation mechanisms bestow cancer cells thermoresistance to protect them from the damage of PTT. To minimize the thermoresistance of cancer cells and improve the efficacy of PTT, an integrated on‐demand nanoplatform composed of a photothermal conversion core (gold nanorod, GNR), a cargo of a HSPs inhibitor (triptolide, TPL), a mesoporous silica based nanoreservoir, and a photothermal and redox di‐responsive polymer shell is developed. The nanoplatform can be enriched in the tumor site, and internalized into cancer cells, releasing the encapsulated TPL under the trigger of intracellular elevated glutathione and near‐infrared laser irradiation. Ultimately, the liberated TPL could diminish thermoresistance of cancer cells by antagonizing the PTT induced heat shock response via multiple mechanisms to maximize the PTT effect for cancer treatment.     

Photosensitizer–Gold Nanorod Composite for Targeted Multimodal Therapy

In this work, a DNA inter‐strand replacement strategy for therapeutic activity is successfully designed for multimodal therapy. In this multimodal therapy, chlorin e6 (Ce6) photosensitizer molecules are used for photodynamic therapy (PDT), while aptamer‐AuNRs, are used for selective binding to target cancer cells and for photothermal therapy (PTT) with near infrared laser irradiation. Aptamer Sgc8, which specifically targets leukemia T cells, is conjugated to an AuNR by a thiol‐Au covalent bond and then hybridized with a Ce6‐labeled photosensitizer/reporter to form a DNA double helix. When target cancer cells are absent, Ce6 is quenched and shows no PDT effect. However, when target cancer cells are present, the aptamer changes structure to release Ce6 to produce singlet oxygen for PDT upon light irradiation. Importantly, by combining photosensitizer and photothermal agents, PTT/PDT dual therapy supplies a more effective therapeutic outcome than either therapeutic modality alone.     

An Intelligent Vascular Disrupting Dendritic Nanodevice Incorporating Copper Sulfide Nanoparticles for Immune Modulation-Mediated Combination Tumor Therapy

Development of intelligent nanoplatforms that can simultaneously target multiple factors associated with tumor growth and metastasis remains an extreme challenge. Here, an intelligent dendritic nanodevice incorporating both copper sulfide nanoparticles (CuS NPs) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a vascular disrupting agent) within the dendrimer internal cavities and surface modified with a targeting agent LyP-1 peptide is reported. The resulting generation 5 (G5) dendrimer-based nanodevice, known as G5-PEG-LyP-1-CuS-DMXAA NPs (GLCD NPs), possess good colloidal stability, pH-sensitive drug release kinetics, and high photothermal conversion efficiency (59.3%). These functional GLCD NPs exert a LyP-1-targeted killing effect on breast tumors by combining CuS-mediated photothermal therapy (PTT) and DMXAA-induced vascular disruption, while also triggering antitumor immune responses through PTT-induced immunogenic cell death and DMXAA-mediated immune regulation via M1 polarization of tumor-associated macrophages and dendritic cell maturation. In addition, with the LyP-1-mediated proapoptotic activity, the GLCD NPs can specifically kill tumor lymphatic endothelial cells. The simultaneous disruption of tumor blood vessels and lymphatic vessels cuts off the two main pathways of tumor metastasis, which plays a two-pronged role in inhibiting lung metastasis of the breast cancer model. Thus, the developed GLCD NPs represent an advanced intelligent nanoformulation for immune modulation-mediated combination tumor therapy with potential for clinical translations.     

Dual Roles of Protein as a Template and a Sulfur Provider: A General Approach to Metal Sulfides for Efficient Photothermal Therapy of Cancer

Fabrication of clinically translatable nanoparticles (NPs) as photothermal therapy (PTT) agents against cancer is becoming increasingly desirable, but still challenging, especially in facile and controllable synthesis of biocompatible NPs with high photothermal efficiency. A new strategy which uses protein as both a template and a sulfur provider is proposed for facile, cost‐effective, and large‐scale construction of biocompatible metal sulfide NPs with controlled structure and high photothermal efficiency. Upon mixing proteins and metal ions under alkaline conditions, the metal ions can be rapidly coordinated via a biuret‐reaction like process. In the presence of alkali, the inert disulfide bonds of S‐rich proteins can be activated to react with metal ions and generate metal sulfide NPs under gentle conditions. As a template, the protein can confine and regulate the nucleation and growth of the metal sulfide NPs within the protein formed cavities. Thus, the obtained metal sulfides such as Ag₂S, Bi₂S₃, CdS, and CuS NPs are all with small size and coated with proteins, affording them biocompatible surfaces. As a model material, CuS NPs are evaluated as a PTT agent for cancer treatment. They exhibit high photothermal efficiency, high stability, water solubility, and good biocompatibility, making them an excellent PTT agent against tumors. This work paves a new avenue toward the synthesis of structure‐controlled and biocompatible metal sulfide NPs, which can find wide applications in biomedical fields.     

A Comparative Study of Clinical Intervention and Interventional Photothermal Therapy for Pancreatic Cancer

Although nanoparticle‐based photothermal therapy (PTT) has been intensively investigated recently, its comparative efficiency with any clinical cancer treatments has been rarely explored. Herein for the first time we report a systematic comparative study of clinical iodine‐125 (¹²⁵I) interstitial brachytherapy (IBT‐125‐I) and interventional PTT (IPTT) in an orthotopic xenograft model of human pancreatic cancer. IPTT, based on the nanoparticles composing of anti‐urokinase plasminogen activator receptor (uPAR) antibody, polyethylene glycol (PEG), and indocyanine green (ICG) modified gold nanoshells (hereinafter uIGNs), is directly applied to local pancreatic tumor deep in the abdomen. In comparison to IBT‐125‐I, a 25% higher median survival rate of IPTT with complete ablation by one‐time intervention has been achieved. The IPTT could also inhibit pancreatic tumor metastasis which can be harnessed for effective cancer immunotherapy. All results show that this IPTT is a safe and radical treatment for eradicating tumor cells, and may benefit future clinical pancreatic cancer patients.     

Functionalized Graphene@Gold Nanostar/Lipid for Pancreatic Cancer Gene and Photothermal Synergistic Therapy under Photoacoustic/Photothermal Imaging Dual‐Modal Guidance

Nanomaterial‐based pancreatic cancer treatment has received widespread attention and rapid development in the past few years. The major challenges include the poor combination of diagnosis and therapy, the difficulty in targeting therapy from the root and the unsatisfactory antitumor efficiency, which is accompanied by a great risk of relapse and metastasis. In this work, a positively charged lipid bilayer membrane is coated on reduced graphene oxide@gold nanostar (rGO@AuNS) for photoacoustic/photothermal dual‐modal imaging‐guided gene/photothermal synergistic therapy of pancreatic cancer. In addition, the cross‐linking of folic acid on the surface of rGO@AuNS‐lipid can specifically bind after recognizing folic acid receptors on the surface of cancer cells, and greatly improve the targeting ability of the nanomaterial and the performance of imaging diagnosis by receptor‐mediated endocytosis. Moreover, the photothermal and gene (targeting G12V mutant K‐Ras gene) synergistic therapy shows outstanding anticancer efficacy for pancreatic cancer tumor bearing mice, and it is noteworthy that the treatment groups have anti‐liver metastasis of pancreatic cancer.     

Graphene Quantum Dots‐Capped Magnetic Mesoporous Silica Nanoparticles as a Multifunctional Platform for Controlled Drug Delivery,Magnetic Hyperthermia,and Photothermal Therapy

A multifunctional platform is reported for synergistic therapy with controlled drug release, magnetic hyperthermia, and photothermal therapy, which is composed of graphene quantum dots (GQDs) as caps and local photothermal generators and magnetic mesoporous silica nanoparticles (MMSN) as drug carriers and magnetic thermoseeds. The structure, drug release behavior, magnetic hyperthermia capacity, photothermal effect, and synergistic therapeutic efficiency of the MMSN/GQDs nanoparticles are investigated. The results show that monodisperse MMSN/GQDs nanoparticles with the particle size of 100 nm can load doxorubicin (DOX) and trigger DOX release by low pH environment. Furthermore, the MMSN/GQDs nanoparticles can efficiently generate heat to the hyperthermia temperature under an alternating magnetic field or by near infrared irradiation. More importantly, breast cancer 4T1 cells as a model cellular system, the results indicate that compared with chemotherapy, magnetic hyperthermia or photothermal therapy alone, the combined chemo‐magnetic hyperthermia therapy or chemo‐photothermal therapy with the DOX‐loaded MMSN/GQDs nanosystem exhibits a significant synergistic effect, resulting in a higher efficacy to kill cancer cells. Therefore, the MMSN/GQDs multifunctional platform has great potential in cancer therapy for enhancing the therapeutic efficiency.     

Tumor‐Targeted Drug and CpG Delivery System for Phototherapy and Docetaxel‐Enhanced Immunotherapy with Polarization toward M1‐Type Macrophages on Triple Negative Breast Cancers

Cancer immunotherapy has achieved promising clinical responses in recent years owing to the potential of controlling metastatic disease. However, there is a limited research to prove the superior therapeutic efficacy of immunotherapy on breast cancer compared with melanoma and non‐small‐cell lung cancer because of its limited expression of PD‐L1, low infiltration of cytotoxic T lymphocytes (CTLs), and high level of myeloid‐derived suppressor cells (MDSCs). Herein, a multifunctional nanoplatform (FA‐CuS/DTX@PEI‐PpIX‐CpG nanocomposites, denoted as FA‐CD@PP‐CpG) for synergistic phototherapy (photodynamic therapy (PDT), photothermal therapy (PTT) included) and docetaxel (DTX)‐enhanced immunotherapy is successfully developed. The nanocomposites exhibit excellent PDT efficacy and photothermal conversion capability under 650 and 808 nm irradiation, respectively. More significantly, FA‐CD@PP‐CpG with no obvious side effects can remarkably inhibit the tumor growth in vivo based on a 4T1‐tumor‐bearing mice modal. A low dosage of loaded DTX in FA‐CD@PP‐CpG can promote infiltration of CTLs to improve efficacy of anti‐PD‐L1 antibody (aPD‐L1), suppress MDSCs, and effectively polarize MDSCs toward M1 phenotype to reduce tumor burden, further to enhance the antitumor efficacy. Taken together, FA‐CD@PP‐CpG nanocomposites offer an efficient synergistic therapeutic modality in docetaxel‐enhanced immunotherapy for clinical application of breast cancer.