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Near‐infrared photoimmunotherapy (NIR‐PIT) is a new type of cancer therapy that employs antibody‐IRDye700DX conjugates (AbPCs) and near‐infrared (NIR) light at a wavelength of 689 nm, the excitation wavelength of IR700. Administered intravenously, injected AbPCs bind specifically to cells expressing the target antigen, whereupon NIR light exposure causes rapid, selective killing. This process induces an anticancer T cell response, leading to sustained anticancer host immune response. Programmed cell death ligand‐1 (PD‐L1) is a major inhibitory immune checkpoint molecule expressed in various cancers. In this study, we first assessed the efficacy of PD‐L1‐targeted NIR‐PIT (αPD‐L1‐PIT) in immune‐competent tumor mouse models. αPD‐L1‐PIT showed a significant therapeutic effect on the tumor models with high PD‐L1 expression. Furthermore, αPD‐L1‐PIT induced an abscopal effect on distant tumors and long‐term immunological memory. In contrast, αPD‐L1‐PIT was not as effective for tumor models with low PD‐L1 expression. To improve the efficacy of PD‐L1‐targeted NIR‐PIT, PEGylated interferon‐gamma (IFNγ) was administered with αPD‐L1‐PIT. The combination therapy improved the treatment efficacy by increasing PD‐L1 expression leading to more efficient cell killing by αPD‐L1‐PIT. Furthermore, the PEGylated IFNγ led to a CD8+ T cell‐dominant tumor microenvironment (TME) with an enhanced anticancer T cell response after αPD‐L1‐PIT. As a result, even so‐called cold tumors exhibited complete responses after αPD‐L1‐PIT. Thus, combination therapy of PEGylated IFNγ and PD‐L1‐targeted NIR‐PIT has the potential to be an important future strategy for cancer immunotherapy. The combination therapy improved the treatment efficacy by increasing programmed cell death ligand‐1 (PD‐L1) expression leading to more efficient cell killing by anti‐PD‐L1 antibody photoimmunotherapy (αPD‐L1‐PIT). Furthermore, the PEGylated interferon‐gamma (IFNγ) led to a CD8+ T cell‐dominant tumor microenvironment (TME) with an enhanced anticancer T cell response after αPD‐L1‐PIT. As a result, even so‐called cold tumors exhibited complete responses after αPD‐L1‐PIT. Thus, combination therapy of PEGylated IFNγ and PD‐L1‐targeted near‐infrared (NIR)‐PIT has the potential to be an important future strategy for cancer immunotherapy.

Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and conventional chemotherapy and molecular‐targeted therapies show limited efficacy. Near‐infrared photoimmunotherapy (NIR‐PIT) is a new anticancer treatment that selectively damages the cell membrane of cancer cells based on NIR light‐induced photochemical reactions of the antibody (Ab)‐photoabsorber (IRDye700Dx) conjugate and the cell membrane. TNBC is known to express several adhesion molecules on the cell surface providing a potential new target for therapy. Here, we investigated the therapeutic efficacy of intercellular adhesion molecule‐1 (ICAM‐1)‐targeted NIR‐PIT using xenograft mouse models subcutaneously inoculated with two human ICAM‐1‐expressing TNBC cell lines, MDAMB468‐luc and MDAMB231 cells. In vitro ICAM‐1‐targeted NIR‐PIT damaged both cell types in a NIR light dose‐dependent manner. In vivo ICAM‐1‐targeted NIR‐PIT in both models showed early histological signs of cancer cell damage, such as cytoplasmic vacuolation. Even among the cancer cells that appeared to be morphologically intact within 2 h post treatment, abnormal distribution of the actin cytoskeleton and a significant decrease in Ki‐67 positivity were observed, indicating widespread cellular injury reflected in cytoplasmic degeneration. Such damage to cancer cells by NIR‐PIT significantly inhibited subsequent tumor growth and improved survival. This study suggests that ICAM‐1‐targeted NIR‐PIT could have potential clinical application in the treatment of TNBC. Early histological changes after in vivo ICAM‐1‐targeted NIR‐PIT.

Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in many cancers, and overexpression of EGFR is frequently observed in hepatocellular carcinomas (HCCs). Near‐infrared photoimmunotherapy (NIR‐PIT) is a new anticancer treatment that selectively damages the cell membrane of cancer cells after NIR light‐induced photochemical reaction of IR700, which is bound to a targeting antibody on the cell membrane. NIR‐PIT using cetuximab‐IR700 has already been approved in Japan, is under review by the US Food and Drug Administration (FDA) for advanced head and neck cancers, and its safety has been established. However, EGFR has not been investigated as a target in NIR‐PIT in HCCs. Here, we investigate the application of NIR‐PIT using cetuximab‐IR700 to HCCs using xenograft mouse models of EGFR‐expressing HCC cell lines, Hep3B, HuH‐7, and SNU‐449. In vitro NIR‐PIT using EGFR‐targeted cetuximab‐IR700 killed cells in a NIR light dose‐dependent manner. In vivo NIR‐PIT resulted in a delayed growth compared with untreated controls. In addition, in vivo NIR‐PIT in both models showed histological signs of cancer cell damage, such as cytoplasmic vacuolation and nuclear dysmorphism. A significant decrease in Ki‐67 positivity was also observed after NIR‐PIT, indicating decreased cancer cell proliferation. This study suggests that NIR‐PIT using cetuximab‐IR700 has potential for the treatment of EGFR‐expressing HCCs. Near‐infrared photoimmunotherapy (NIR‐PIT) was effective to hepatocellular carcinoma (HCC) tumors.

Near‐infrared photoimmunotherapy (NIR‐PIT) is a new cancer phototherapy modality using an antibody conjugated to a photosensitizer, IRDye700DX. When the conjugate binds to the plasma membrane and is exposed to NIR light, NIR‐PIT‐treated cells undergo swelling, and target‐selective necrotic/immunogenic cell death is induced. However, the cytotoxic mechanism of NIR‐PIT has not been elucidated. In order to understand the mechanism, it is important to elucidate how the damage to the plasma membrane induced by NIR light irradiation changes over time. Thus, in the present study, we investigated the changes in plasma membrane permeability using ions and molecules of various sizes. Na+ flowed into cells immediately after NIR light irradiation, even when the function of transporters or channels was blocked. Subsequently, fluorescent molecules larger than Na+ entered the cells, but the damage was not large enough for dextran to pass through at early time points. To assess these phenomena quantitatively, membrane permeability was estimated using radiolabeled ions and molecules: 111InCl3, 111In‐DTPA, and 3H‐H2O, and comparable results were obtained. Although minute plasma membrane perforations usually do not induce cell death, our results suggest that the minute damage induced by NIR‐PIT was irreversibly extended with time. In conclusion, minute plasma membrane damage is a trigger for the increase in plasma membrane permeability, cell swelling, and necrotic/immunogenic cell death in NIR‐PIT. Our findings provide new insight into the cytotoxic mechanism of NIR‐PIT. In the present study, the cytotoxic mechanism of photoimmunotherapy was investigated. As a result, we found that minute irreversible damage of the cell plasma membrane was produced after near‐infrared light irradiation. This damage was not recovered in the usual biological process, but it was expanded to cause fatal cell death.

Near‐infrared photoimmunotherapy (NIR‐PIT) is a recently approved cancer therapy utilizing an antibody conjugated to IR700 dye which is injected and then followed with focal NIR light. NIR‐PIT is ideal for focal therapy of cancer because of its cell specificity and minimal invasiveness compared to surgical resection. Most treatment‐emergent adverse events are low grade and include edema, fatigue, and pain. However, edema in specific anatomic locations could lead to significant complications, such as airway obstruction, and thus, it is desirable to reduce edema if possible. Edema and the resulting pain are likely precipitated by reactive oxygen species generated primarily from the interaction of laser light with unbound antibody–photoabsorber conjugate. These reactive species can be neutralized by reducing agents, such as vitamin C, a potent reducing agent and proton donor. Based on its photochemical mechanisms, we hypothesized that pretreating patients with L‐sodium ascorbate (L‐NaAA) will reduce NIR‐PIT‐induced edema. Here, we evaluated the effect of L‐NaAA concentration on edema as well as its effect on the immune responses after NIR‐PIT. L‐NaAA demonstrated concentration‐dependent inhibition of edema after NIR‐PIT without compromising the efficacy of NIR‐PIT. Furthermore, L‐NaAA did not impede the anticancer immune activation elicited by NIR‐PIT, nor did it affect the efficacy of Treg‐targeted NIR‐PIT. NIR‐PIT groups, both with and without L‐NaAA, significantly inhibited tumor growth and resulted in markedly prolonged survival compared to the control group, but those with L‐NaAA had reduced edema. Thus, L‐NaAA may serve as a useful adjunct to NIR‐PIT, enhancing its safety profile without detracting from its therapeutic efficacy. Acute temporal edema, which can potentially obstruct the airway, is the most common adverse effect associated with near‐infrared photoimmunotherapy (NIR‐PIT) of head and neck cancer. Leveraging the chemical mechanisms of NIR‐PIT, vitamin C has been shown to suppress such edema and enhance cytotoxicity by quenching reactive oxygen species and donating protons. This study demonstrates that the administration of vitamin C during NIR‐PIT effectively suppresses local edema while simultaneously enhancing therapeutic efficacy, all without compromising the host immune response.

Near‐infrared photoimmunotherapy (NIR‐PIT) is a novel antitumor therapy that selectively kills cancer cells by NIR light‐triggered photochemical reaction of IRDye700DX within Ab–photoabsorber conjugates (APCs). NIR‐PIT induces immunogenic cell death, causing immune cell migration between the tumor and tumor‐draining lymph nodes, and expanding multiclonal tumor‐infiltrating CD8+ T cells. Crucially, the cytotoxic effects of NIR‐PIT are limited to cancer cells, sparing immune cells such as antigen‐presenting cells and T cells, which are key players in boosting antitumor host immunity. By modifying the Ab used in APC synthesis, NIR‐PIT can be repurposed to target and deplete noncancerous immunosuppressive cells including regulatory T cells, myeloid‐derived suppressor cells, and cancer‐associated fibroblasts in the tumor microenvironment. Immunosuppressive cell targeted NIR‐PIT strongly potentiates antitumor host immunity, including the induction of abscopal effects and the development of immune memory. Furthermore, antitumor immune responses and therapeutic efficacy are synergistically enhanced when NIR‐PIT is combined with other immune‐activating treatments, such as interleukin‐15 and immune checkpoint inhibitors. These new findings make NIR‐PIT a valuable tool in the evolving landscape of cancer immunotherapy. This review explains the role of NIR‐PIT in activating antitumor host immunity. Near‐infrared photoimmunotherapy (NIR‐PIT) is a novel antitumor therapy that selectively kills cancer cells by NIR light‐triggered transformation of IRDye700DX within Ab–photoabsorber conjugates (APCs). NIR‐PIT effectively induces immunogenic cell death, immune cell migration between the tumor and tumor‐draining lymph node, and expansion of multiclonal tumor‐infiltrating CD8+ T cells. Crucially, cytotoxic effects of NIR‐PIT exert only cancer cells, sparing immune cells such as antigen‐presenting cells and T cells, key players in boosting antitumor host immunity. By modifying the Ab used in APC synthesis, NIR‐PIT can target and deplete noncancerous immunosuppressive cells including regulatory T cells, myeloid‐derived suppressor cells, and cancer‐associated fibroblasts, in the tumor microenvironment. Immunosuppressive cell‐targeted NIR‐PIT strongly potentiate antitumor host immunity, including the induction of abscopal effects and the development of immune memory. Furthermore, antitumor immune responses and therapeutic efficacy are synergistically enhanced when combining NIR‐PIT with other immune‐activating treatments, such as interleukin‐15 and immune checkpoint inhibitors. This evidence identifies NIR‐PIT as a valuable tool in the evolving landscape of cancer immunotherapy. This review presents the role of NIR‐PIT in activating antitumor host immunity.

Near‐infrared photoimmunotherapy (NIR‐PIT) is a tumor‐specific treatment using monoclonal antibody (mAb) photosensitizer conjugates, followed by near‐infrared light irradiation. This study aimed to identify the optimum target for treating esophagogastric junction (EGJ) adenocarcinoma and to evaluate the efficacy of NIR‐PIT using mAbs in preclinical models. Tumor samples from 46 consecutive patients who had undergone surgery without any prior treatment for EGJ adenocarcinoma were assessed for expression and homogeneity of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and epithelial cell adhesion molecule (EpCAM) through immunohistochemistry. Results showed positive rates of 22%, 13%, and 98% for EGFR, HER2, and EpCAM, respectively, with EpCAM also demonstrating the highest homogeneity (93%). Therefore, EpCAM was selected as the optimal target for NIR‐PIT. The fully human monoclonal antibody targeting EpCAM, adecatumumab, was conjugated with the photosensitizer IR700 at different dye‐antibody ratios (DAR2, DAR4, DAR7) and tested on OE19 cells and xenograft mouse models under near‐infrared light irradiation. NIR‐PIT with adecatumumab‐IR700 significantly reduced tumor size and improved prognoses compared to controls, with DAR2 showing the best balance of efficacy and minimal side effects. Notable EpCAM expression and homogeneity underpin EpCAM as a promising target for NIR‐PIT in EGJ adenocarcinoma. The fully human anti‐EpCAM antibody may be suitable for NIR‐PIT in EGJ adenocarcinoma. Photoimmunotherapy (PIT) in vitro. OE19 cells formed blisters 3 h after laser illumination using adecatumumab‐IR700.

Near‐infrared photoimmunotherapy (NIR‐PIT) is a novel therapy for cancers that uses NIR light and antibody‐photosensitizer (IR700) conjugates. However, it is difficult to deliver NIR light into the bile duct for cholangiocarcinoma (CCA) from the conventional extracorporeal apparatus. Thus, in this study, we developed a dedicated catheter with light emitting diodes (LEDs) that supersedes conventional external irradiation devices; we investigated the therapeutic effect of NIR‐PIT for CCA using the novel catheter. The new catheter was designed to be placed in the bile duct and a temperature sensor was attached to the tip of the catheter to avoid thermal burn. An anti‐epidermal growth factor receptor (EGFR) antibody, Panitumumab‐IR700 conjugate or anti‐human epidermal growth factor receptor type 2 (HER2) antibody, Trastuzumab‐IR700 conjugate, was used with EGFR‐ or HER2‐expressing cell lines, respectively. The in vitro efficacy of NIR‐PIT was confirmed in cultured cells; the capability of the new catheter for NIR‐PIT was then tested in a mouse tumor model. NIR‐PIT via the developed catheter treated CCA xenografts in mice. NIR‐PIT had an effect in Panitumumab‐IR700 conjugate‐ and Trastuzumab‐IR700 conjugate‐treated CCA cells that depended on the receptor expression level. Tumor growth was significantly suppressed in mice treated with NIR‐PIT using the novel catheter compared with controls (P < .01). NIR‐PIT was an effective treatment for EGFR‐ and HER2‐expressing CCA cells, and the novel catheter with mounted LEDs was useful for NIR‐PIT of CCA. A new catheter with light emitting diodes for photoimmunotherapy for cholangiocarcinoma was developed. The new catheter was designed to be placed in the bile duct and a temperature sensor was attached to the tip of the catheter to avoid thermal burn. Tumor growth was significantly suppressed in mice treated with NIR‐PIT using the novel catheter.

Among modalities of cancer immunotherapy, near‐infrared photoimmunotherapy (NIR‐PIT) has reached significant preclinical and clinical stages and quickly evolved over the last 5 years. NIR‐PIT uses deep‐penetrable NIR light to induce physicochemical changes in the antibody–photosensitizer conjugate (APC), leading to resultant necrosis and immunogenic cell death (ICD) of the cancer cells. Alternatively, other types of photomedicine use photosensitizers to convert absorbed light energy either into reactive oxygen species for photodynamic therapy (PDT) or into heat for photothermal therapy (PTT). ICD is a unique and relevant outcome of NIR‐PIT because it induces long‐lasting antitumor host immunity, which overcomes the immunosuppressive network of cancer. Due to its high specificity and durable antitumor effects, NIR‐PIT is now considered a promising cancer therapy, and optimized NIR‐PIT is readily expanding its applicability to many different types of cancer. Along with the traditional method of NIR‐PIT, new avenues in its realm of treatment are currently being explored, such as the targeting of other immunosuppressive elements, delivery of NIR light through a catheter, real‐time imaging for tumor detection, and the use of tumor‐seeking small molecules for improved efficacy and safety. In addition, its effect on hyperpermeability has opened a door for a wide array of combination therapies with other modalities. This review summarizes the recent findings in clinical and preclinical studies of NIR‐induced photomedicine and its future significance in the field of cancer research. Near‐infrared photoimmunotherapy (NIR‐PIT), which demonstrated recent preclinical and clinical success, is an expansion on the field of photomedicine. NIR‐PIT shows remarkable therapeutic effects inducing long‐lasting antitumor host immunity via inducing immunogenic cell death and would soon establish a new class of cancer therapy. Compared to other photomedicines inducing weak immune responses, NIR‐PIT evokes robust anticancer immunity via release of damage‐associated molecular patterns.

Near‐infrared photoimmunotherapy (NIR‐PIT) is a molecularly targeted cancer phototherapy that is based on injecting a conjugate of a silicon‐phthalocyanine derivative, IRdye 700DX (IR700), and a monoclonal antibody that targets an expressed antigen on the cancer cell surface. Subsequent local exposure to NIR light results in the rapid and highly selective immunogenic cell death of targeted cancer cells. Because many cancers grow in bones through which light does not penetrate well, the goal of this study was to determine if NIR‐PIT can effectively treat cancers in bone. A bovine rib was used as a bone sample. Because the sample’s NIR light transmittance was shown to be approximately 4.52% in preliminary tests, it was hypothesized that a maximum radiation dosage of 128 and 1500 J/cm2 would be sufficient to induce cell death in in vitro target cells and in vivo mouse tumor models, respectively. Cell viability was measured through bioluminescence studies comparing relative luciferase activity, as well as a cytotoxicity assay. In the in vitro model, tumor cell viability was significantly decreased after 64 and 128 J/cm2 NIR light irradiation through the bone. An in vivo mouse tumor model also showed that 1500 J/cm2 NIR light irradiation through the bone significantly reduced tumor viability at both 24 and 48 hours posttreatment compared to the control group (P = .026 and .040 respectively). Therefore, despite limitations in light transmission, NIR‐PIT nevertheless is capable of effectively treating cancers within bone. Tumors were successfully treated through a bovine bone sample.