Antitumor host immunity enhanced by near‐infrared photoimmunotherapy

Abstract

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.

Abbreviations

• APC
• Ab–photoabsorber conjugate
• CAF
• cancer-associated fibroblast
• cDC1
• type-1 conventional dendritic cell
• cDC2
• type-2 conventional dendritic cell
• CEA
• carcinoembryonic antigen
• CTLA4
• cytotoxic T lymphocyte-associated protein 4
• DAMP
• damage-associated molecular pattern
• DC
• dendritic cell
• EGFR
• epidermal growth factor receptor
• FAP
• fibroblast activation protein
• HER2
• human epidermal growth factor receptor-2
• HMGB1
• high mobility group box 1
• HNSCC
• head and neck squamous cell carcinoma
• HSP
• heat shock protein
• ICAM-1
• intercellular adhesion molecule-1
• ICD
• immunogenic cell death
• ICI
• immune checkpoint inhibitor
• IL
• interleukin
• IR700
• IRDye700DX
• MDSC
• myeloid-derived suppressor cell
• M-MDSC
• monocytic myeloid-derived suppressor cell
• NIR
• near-infrared
• NIR-PIT
• near-infrared photoimmunotherapy
• NK
• natural killer
• PACT
• phototruncation-assisted cell tracking
• PD-1
• programmed cell death protein 1
• PD-L1
• programmed cell death ligand-1
• PMN-MDSC
• polymorphonuclear myeloid-derived suppressor cell
• PSMA
• prostate-specific membrane antigen
• TDLN
• tumor-draining lymph node
• Treg
• regulatory T cell
• VISTA
• V-domain Ig suppressor of T cell activation

INTRODUCTION

Near-infrared photoimmunotherapy (NIR-PIT) is a novel, molecular-targeted therapy that selectively kills cancer cells as a consequence of photochemical reactions within Ab–photoabsorber conjugates (APCs) on cancer cell membranes (Figure 1).^1,2 In the synthesis of APCs, the photoabsorber IRDye700DX (IR700), a silica-phthalocyanine dye, is classically conjugated to a mAb directed against a cancer-associated protein on cancer cell membrane.³ Approximately 24 h after APC administration, which allows enough time for sufficient binding on the target cell, near-infrared (NIR) light is applied to the tumor site, triggering photochemical cascades that lead to selective cancer cell killing through lethal cell membrane injury while leaving adjacent healthy normal tissues unaffected.⁴ In comparison to traditional cancer therapies such as surgery, radiotherapy, and chemotherapy, NIR-PIT possesses distinct therapeutic advantages, specifically its high selectivity to cancer cells and its potential to bolster antitumor host immunity. NIR-PIT can effectively induce immunogenic cell death (ICD) of cancer cells and the maturation of DCs, resulting in increased cross-priming of cancer-associated antigens.⁵ Also, NIR-PIT can target and deplete noncancerous immunosuppressive cells in the tumor microenvironment by targeting antigens on these cells (Figure 2).¹ The NIR-PIT targeting of immunosuppressive cells induces a strong antitumor immune activation.¹

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In this review, we present the basis and current status of NIR-PIT and summarize how NIR-PIT activates antitumor host immunity, especially focusing on the induction of ICD and subsequent immune cell migration. We further review antitumor immune responses following NIR-PIT targeting of immunosuppressive cells. Moreover, we discuss synergistic enhancement of antitumor immune responses when combining cancer cell-targeted NIR-PIT with other immune-activating treatments, such as immunosuppressive cell-targeted NIR-PIT, immune checkpoint inhibitors (ICIs), and interleukin (IL)-15.

BASIS AND CURRENT STATUS OF NIR-PIT

Cytotoxic mechanism of NIR-PIT

NIR-PIT selectively targets cancer cells when the mAb of the APC binds target cells. NIR light then triggers photochemical reactions within the APCs (Figure 1).^1,2 The APCs are synthesized by conjugating IR700 to a mAb specific to a cell membrane protein that is highly and exclusively expressed on specific target cells, whether they are cancer cells or immune cells.³ APCs are infused i.v., and selectively bind to specific antigens present on the surface of the cells. Approximately 24 h after the injection of APCs, 690 nm NIR light is irradiated to the target. NIR light induces the dissociation of axial ligands from the IR700 molecule, leading to a transformation from a highly hydrophilic to a highly hydrophobic molecule (Figure 3).⁴ This photochemical reaction facilitates APC aggregation and disrupts the integrity of the cell membrane while sparing adjacent healthy normal tissues that lack the targeting antigen, including immune cells that are important in activating antitumor host immunity.⁴ Immediately after starting NIR light irradiation, cells show swelling, blebbing, and bursting, resulting in necrotic cell death.⁶ These cytotoxic mechanisms in NIR-PIT are completely different from those in conventional photodynamic therapy and photothermal therapy, in which generated reactive oxygen species nonspecifically injure cancer cells and adjacent healthy normal tissues,^7,8 and those in Ab-drug conjugates that allow for the targeted release of cytotoxic payload in cancer cells.⁹ Moreover, because of the harmlessness of NIR light by itself and the cell-selective nature of NIR-PIT, NIR-PIT can be repeatedly applied to the same target lesion, especially in the treatment of residual or recurrent tumors.¹⁰

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Current status of clinical applications of NIR-PIT

Our previous preclinical studies showed high therapeutic efficacy of NIR-PIT targeting epidermal growth factor receptor (EGFR), one of the most important therapeutic targets in oncology.^11–14 This led to clinical trials of EGFR-targeted NIR-PIT in patients with head and neck squamous cell carcinoma (HNSCC) because HNSCC highly expresses EGFR.¹⁵ A phase I/IIa, first-in-human, open-label, multicenter trial showed tolerable and manageable side effects in patients with heavily pretreated recurrent HNSCC.¹⁶ A phase III randomized controlled study of EGFR-targeted NIR-PIT for recurrent HNSCC patients is currently ongoing. In 2020, the first APC for clinical use, a cetuximab-IR700 conjugate (Akalux; Rakuten Medical Inc.), along with a NIR laser system (BioBlade; Rakuten Medical Inc.), received approval from the Pharmaceuticals and Medical Devices Agency in Japan and is now part of the treatment for advanced HNSCC. Recently, real-world data of EGFR-targeted NIR-PIT have shown its high objective response rates (89%) in clinical practice.¹⁷ Also, side effects such as edema and pain are reported in clinical settings.¹⁸ Nonopioid and opioid analgesics are effective in pain management.¹⁸ As laryngeal edema can cause airway obstruction, a tracheostomy is required before NIR light irradiation when treating areas near the airway.¹⁸ Because these side effects are caused by reactive oxygen species produced mainly by the exposure of NIR light to unbound APC, reducing agents, including ascorbic acid, can be effective.¹⁹ For cancers other than HNSCC, a phase II study of EGFR-targeted NIR-PIT for gynecologic cancers has started. Furthermore, recent preclinical studies have shown the effectiveness of NIR-PIT to target various other cancer-associated proteins, such as human epidermal growth factor receptor-2 (HER2),²⁰ carcinoembryonic antigen (CEA),²¹ prostate-specific membrane antigen (PSMA),²² Nectin-4,²³ intercellular adhesion molecule-1 (ICAM-1),²⁴ and programmed cell death ligand-1 (PD-L1).²⁵ These efforts may further expand the clinical application of NIR-PIT to cancers other than HNSCC in the future.

ENHANCEMENT OF ANTITUMOR HOST IMMUNITY BY NIR-PIT

Induction of ICD

ICD is mediated by the relocation and extracellular emission of damage-associated molecular patterns (DAMPs) from dying cancer cells, which significantly potentiate antitumor host immunity.^26,27 The cytotoxic process of NIR-PIT is marked by the induction of ICD. NIR-PIT leads to the massive release of DAMPs from dying cancer cells into the extracellular environment.⁵ These DAMPs, including calreticulin, heat shock protein (HSP) 70, HSP 90, ATP, and high mobility group box 1 (HMGB1), serve as critical signals to the immune system.²⁶ The cellular mechanics underlying NIR-PIT-induced cell death are noteworthy. Following activation by NIR light, the APCs cause rapid and irreversible damage to the cell membrane. This damage precipitates a cascade of events, beginning with the influx of water into the cell, leading to cell rupture.⁴ This is crucial as it facilitates the release of intracellular contents, including many cancer-associated antigens and DAMPs, into the extracellular environment. Our previous study showed that HER2-targeted NIR-PIT caused the relocation of calreticulin, HSP 70, and HSP 90 to the cell surface of dying cancer cells and the rapid release of HMGB1 and ATP.⁵ Furthermore, cell surface expression of calreticulin and HSP 70 were significantly increased after NIR-PIT targeting EGFR,¹² CD44,²⁸ and Nectin-4.²³ The relocation and extracellular release of DAMPs plays a pivotal role in stimulating the host immune system, first by promoting the maturation and activation of dendritic cells (DCs). This process is evidenced by the increased expression of specific surface markers on DCs, including CD80, CD83, CD86, and MHC class II molecules.²⁶ Furthermore, the interaction between NIR-PIT-treated cancer cells and DCs stimulates the production of IL-12, a proinflammatory cytokine that promotes T helper type 1 differentiation, when cocultured with NIR-PIT-treated tumor cells.⁵

Migration of antigen-presenting cells from tumor to TDLN

The immune-activating mechanism of NIR-PIT involves the migratory dynamics of immune cells between the tumor and tumor-draining lymph nodes (TDLNs) following NIR-PIT. DCs phagocytose dying cancer cells, leading to DC maturation. CD44-targeted NIR-PIT significantly enhanced the migration of DC subsets, including type-1 conventional DCs (cDC1s), type-2 conventional DC2 (cDC2s), and CD326⁺ DCs, to the TDLN as observed in photoconvertible KikGR mice.²⁹ This migration was abolished by blocking ATP or Gαi signaling, suggesting a significant role for ATP-mediated immunogenic signals and Gαi protein-coupled receptor pathways in mediating the migration of DCs from the tumor to the TDLN.²⁹ Furthermore, we have recently shown that the migration of DCs and macrophages from the tumor to the TDLN significantly increased immediately after EGFR-targeted NIR-PIT using phototruncation-assisted cell tracking (PACT), which is a novel cell tracking based on NIR light-triggered photoconversion of heptamethine cyanine to pentamethine cyanine.³⁰ The EGFR-targeted NIR-PIT significantly increased the migration of DC subsets, including cDC1s, cDC2s, CD83⁺ DCs, and CD86⁺ DCs, from the tumor to the TDLN, which was regulated by the sphingosine-1-phosphate pathway or Gαi signaling as shown by inhibition experiments that significantly suppressed their migration.³⁰ In addition, proinflammatory M1 macrophages significantly migrated from the tumor to the TDLN, but there was no significant increase in the migration of M2 macrophages.³⁰ The results of these two studies indicate that NIR-PIT enhances the migration of antigen-presenting cells from the tumor to the TDLN.

Expansion of multiclonal tumor-infiltrating CD8⁺ T cells

Upon reaching the TDLN, antigen-presenting cells efficiently prime cancer-associated antigens to naïve CD8⁺ T cells, thereby inducing the activation and proliferation of cytotoxic CD8⁺ T cells. This process is crucial for initiating and maintaining a systemic antitumor immune response. After the priming of naïve CD8⁺ T cells, multiclonal CD8⁺ T cells, specific to certain cancer-associated antigens, are generated in the TDLN. The presence of multiclonal CD8⁺ T cells within the tumor microenvironment can contribute to improved tumor control and long-term survival.³¹ Our previous studies reported a significant increase of multiclonal CD8⁺ T cells in the TDLN after CD44 and EGFR-targeted NIR-PIT.^32,33 The development of multiclonal CD8⁺ T cells in the TDLNs is followed by their migration back to the tumor. We observed an efficient migration of CD8⁺ T cells from the TDLN to the tumor following EGFR-targeted NIR-PIT using the PACT method.³⁰ This migration dramatically transforms the tumor microenvironment from an “immune-cold” to an “immune-hot” state,³⁰ indicating enhanced local antitumor immune responses. Furthermore, NIR-PIT eventually induces the differentiation of CD8⁺ memory T cells, indicating the development of antitumor immune memory by NIR-PIT.³³

Enhancement of antitumor host immunity with immunosuppressive cell-targeted NIR-PIT

Regulatory T cell (Treg)-targeted NIR-PIT

Regulatory T cells are a subset of T cells that play a crucial role in maintaining immune tolerance and suppressing antitumor immunity through multiple mechanisms, including limiting IL-2 availability for effector cells, cytotoxic T lymphocyte-associated protein 4 (CTLA4)-mediated inhibition of DCs, ATP degradation by CD39/CD73, and secretion of immunosuppressive cytokines including IL-10.³⁴ The presence of Tregs within the tumor microenvironment is associated with poor prognosis.³⁵ Consequently, Tregs have emerged as a promising target in cancer immunotherapy. However, targeting all Tregs in the entire body could have dire side effects due to unrestricted activation of the immune system. NIR-PIT can locally and selectively target and deplete Tregs by using mAb that targets Treg-specific markers without causing systemic side effects.

In our previous study, CD25-targeted NIR-PIT demonstrated selective depletion of tumor-infiltrating Tregs.^36,37 CD25, a subunit of the IL-2 receptor, represents an ideal target for Treg-directed therapies due to its high expression on intratumoral Tregs.³⁸ CD25-targeted NIR-PIT induced significant activation of CD8⁺ T and natural killer (NK) cells not only in the treated tumor but also in other, untreated tumors in the same syngeneic mouse model.³³ This systemic antitumor immune activation resulted in significant regression of untreated tumors, representing the “abscopal” effect.³⁶ Furthermore, we demonstrated that NIR-PIT targeting CTLA4, an immune checkpoint molecule that is highly expressed in Tregs, also significantly removed intratumoral Tregs.^39,40 The CTLA4-targeted NIR-PIT enhanced systemic antitumor immunity and induced an increase in cytotoxic CD8⁺ T cell infiltration into tumors, again, resulting in abscopal effects.³⁹ In other studies, intratumoral Tregs were selectively killed by NIR-PIT targeting V-domain Ig suppressor of T cell activation (VISTA), a checkpoint molecule expressed on lymphoid and myeloid cells including Tregs and myeloid-derived suppressor cells (MDSCs).⁴¹ VISTA-targeted NIR-PIT reprogrammed the tumor microenvironment to a more immunostimulatory state by removing immunosuppressive cells including Tregs.⁴² Thus, selective targeting of Tregs and related cells by NIR-PIT is a promising therapeutic approach that alleviates the immunosuppressive effects of intratumoral Tregs without incurring the systemic side effects associated with total body depletion, thereby allowing a more robust immune response against the tumor.

MDSC-targeted NIR-PIT

MDSCs are immunosuppressive cells commonly found in the tumor microenvironment.⁴³ MDSCs interfere with the maturation of DCs and suppress T cells by producing arginase-1, inducible nitric oxide synthase, and IL-10.⁴³ There are two main subsets of MDSCs: polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs). M-MDSCs suppress T cells in both antigen-specific and nonspecific ways, whereas PMN-MDSCs primarily act in an antigen-specific manner.⁴⁴

Ly6G-targeted NIR-PIT successfully depleted intratumoral PMN-MDSCs, allowing T cells and NK cells to better attack the tumor and making the tumor environment more immunostimulatory.⁴⁵ PMN-MDSC depletion by NIR-PIT not only suppressed the growth of the treated tumors but also induced abscopal effects.⁴⁵ However, Ly6G cannot target human MDSCs as it is a surface antigen specific to mice. As an alternative, NIR-PIT targeting VISTA, which is expressed both on PMN-MDSCs and M-MDSCs, significantly depleted PMN-MDSCs and M-MDSCs in addition to Tregs in the tumor, resulting in enhanced antitumor immunity.⁴² Therefore, MDSC-targeted NIR-PIT is a potential therapeutic approach to enhance antitumor immunity and induce systemic tumor regression.

Cancer-associated fibroblast (CAF)-targeted NIR-PIT

CAFs are a major component of the tumor microenvironment and play a pivotal role in tumor invasion, metastasis, immune evasion, and resistance to therapy.⁴⁶ Cancer-associated fibroblasts contribute to tumor progression by remodeling the extracellular matrix, trapping immune cells in the tumor stroma, promoting angiogenesis, and secreting immunosuppressive cytokines.⁴⁶ These activities create a physical and immunological barrier that protects tumor cells from immune surveillance and therapeutic interventions.⁴⁶

Fibroblast activation protein (FAP)-targeted NIR-PIT induced rapid death of CAFs in the tumor microenvironment and significantly inhibited tumor growth in human esophageal cancer xenograft models.⁴⁷ Moreover, FAP-targeted NIR-PIT overcame 5-fluorouracil resistance by eliminating CAF stimulation to cancer cells.⁴⁸ In syngeneic murine tumor models, FAP-targeted NIR-PIT enhanced antitumor immunity, resulting in increased tumor-infiltrating CD8⁺ T cells and upregulation of proinflammatory cytokines in the tumor.⁴⁹ Abscopal effects were induced in lung metastases by FAP-targeted NIR-PIT using a spontaneous mammary cancer model.⁵⁰ Recently, NIR-PIT using sibrotuzumab, a humanized IgG1 mAb targeting FAP, showed suppression of tumor progression in patient-derived xenograft models of esophageal cancer,⁵¹ demonstrating the preclinical evidence of high therapeutic efficacy of FAP-targeted NIR-PIT. These findings suggest that FAP could be another target for immune-targeted NIR-PIT.

Podoplanin is highly expressed not only in various cancers such as angiosarcomas, chondrosarcomas, osteosarcomas, and germ-cell tumors but also in a subset of stromal cells, particularly CAFs.⁵² Podoplanin-targeted NIR-PIT selectively destroyed podoplanin-expressing cancer cells and CAFs, suppressing tumor progression and prolonging survival.⁵³ Importantly, podoplanin-targeted NIR-PIT also showed therapeutic efficacy in tumor models that do not express podoplanin in cancer cells, indicating a distinct immunologic effect.⁵³ Moreover, podoplanin-targeted NIR-PIT significantly increased cytotoxic CD8⁺ T cells in the tumor.⁵³ Thus, podoplanin is also considered a promising target in immune-targeted NIR-PIT.

NIR-PIT simultaneously targeting cancer cells and immunosuppressive cells

Cancer cell-targeted NIR-PIT can be combined with immunosuppressive cell-targeted NIR-PIT. Simultaneous depletion of cancer cells and Tregs by NIR-PIT targeting CD44/CD25,⁵⁴ EGFR/CD25,³³ or EGFR/CTLA4⁵⁵ showed significant enhancement of antitumor immune responses and synergistic therapeutic efficacy. Moreover, the simultaneous depletion of cancer cells and CAFs by NIR-PIT targeting EGFR/FAP or HER2/FAP showed significant therapeutic efficacy in immunodeficient mice inoculated with human cancer cell lines.⁵⁶ Thus, NIR-PIT simultaneously targeting cancer cells and immunosuppressive cells is considered a potentially additive or synergistic treatment strategy.

Combination of NIR-PIT with immune-activating agents

NIR-PIT combined with IL-15

Interleukin-15 is a potent cytokine known for its ability to stimulate the proliferation and activation of NK and CD8⁺ T cells.⁵⁷ Unlike IL-2 that promotes the expansion of Tregs, IL-15 is not present on Tregs and thus, selectively promotes antitumor immunity.⁵⁷ As IL-15 monotherapy promotes nonspecific immunity,⁵⁸ it would be more effective when combined with other cancer-killing therapies that result in the release of tumor antigens and stimulate antitumor acquired immunity. Thus, IL-15 would be ideal for use with NIR-PIT. In our previous study, CD44-targeted NIR-PIT was combined with i.p. injections of IL-15 in multiple syngeneic murine tumor models.⁵⁹ This combination therapy resulted in the slowest tumor growth and the best survival compared to the control or either therapy alone.⁵⁹

Intravenous infusion of IL-15 can cause side effects because it extensively expands peripheral NK cells, resulting in higher rates of severe dose-limiting toxicity.⁶⁰ Meanwhile, local administration of IL-15 directly into the tumor can enhance its delivery to the tumor microenvironment while minimizing systemic toxicity. Thus, we combined CD44-targeted NIR-PIT with intratumoral delivery of IL-15. The combination of CD44-targeted NIR-PIT and intratumoral administration of IL-15 significantly boosted antitumor immunity, led to the maturation of DCs, and increased the number of tumor-infiltrating CD8⁺ T, NK, and natural killer T cells.²⁸ Moreover, this combination therapy resulted in significant tumor control, abscopal effects in the untreated tumor, and the development of immune memory.²⁸

NIR-PIT combined with ICIs

Immune checkpoint inhibitors have become an important mainstay of cancer therapy. Programmed cell death protein 1 (PD-1) is an immune checkpoint that downregulates T cell activity.⁶¹ Tumors often exploit this pathway to evade immune surveillance. Anti-PD-1 mAb reinvigorates exhausted T cells and enhances T cell-mediated antitumor immune responses by blocking the interaction between PD-1 and its ligands.⁶¹ Additionally, anti-CTLA4 mAb targets the CTLA4 receptor on T cells, including Tregs, promoting T cell activation and proliferation by preventing the binding of CTLA4 to CD80/CD86 on antigen-presenting cells, which inhibits T cell activation.⁶² Immune checkpoint inhibitors are good candidates to be used in combination with NIR-PIT to elicit more potent antitumor immune responses. ASP-1929-181, a phase Ib/II open-label study of EGFR-targeted NIR-PIT combined with anti-PD-1 mAb in recurrent HNSCC shows a promising interim result (overall survival at 24 months, 52.4%), suggesting its effectiveness in a clinical setting.⁶³

Blockade of PD-1 combined with CD44-targeted NIR-PIT robustly enhanced systemic antitumor immunity, resulting in complete remission rates of 70% in some models as well as abscopal effects in untreated tumors, and resistance to tumor rechallenge in immunogenic MC38 tumors.³² Similar results were observed with EphA2-targeted NIR-PIT combined with PD-1 blockade.⁶⁴ Of note, in a poorly immunogenic tumor model that would not be predicted to respond to ICIs, CD44-targeted NIR-PIT effectively increased CD8⁺ T cell infiltration and immune activation in the tumor⁶¹ that, when combined with PD-1 blockade, led to significant tumor growth inhibition and improved survival.⁶⁵

Blockade of CTLA4 combined with CD44-targeted NIR-PIT had greater tumor growth inhibition with prolonged survival compared to CTLA4 blockade alone.⁶⁶ Moreover, CTLA4 blockade combined with CD29-targeted NIR-PIT increased the infiltration of CD8⁺ T cells and induced tumor growth suppression with prolonged survival in a pigmented melanoma model.⁶⁷ Therefore, cancer cell-targeted NIR-PIT in combination with ICIs offers a promising approach to enhance the efficacy of cancer immunotherapy. The ability of NIR-PIT to enhance the efficacy of ICIs highlights its immune-stimulating potential, making it a key component of combination immunotherapy regimens.

CONCLUSION

NIR-PIT is an effective cancer immunotherapy that activates antitumor host immunity (Figure 4). NIR-PIT substantially and rapidly induces ICD in cancer cells, releasing DAMPs that stimulate DC maturation and orchestrating a complex series of immune cell migrations between the tumor and TDLN. These processes ultimately lead to significant infiltration of cytotoxic effector T cells within the tumor. Moreover, NIR-PIT can enhance systemic antitumor immune responses by targeting immunosuppressive cells such as Tregs, MDSCs, and CAFs. Simultaneously targeting cancer cells and immunosuppressive cells in NIR-PIT further potentiates host immune responses and therapeutic effects. When combined with other immunotherapies such as IL-15 or ICIs, NIR-PIT has the potential to synergistically enhance antitumor immune responses. These combined approaches can lead to more potent antitumor effects, further expanding the role of NIR-PIT as a valuable tool in the evolving landscape of cancer immunotherapy.

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AUTHOR CONTRIBUTIONS

Hiroshi Fukushima: Investigation; visualization; writing – original draft. Aki Furusawa: Writing – review and editing. Ryuhei Okada: Writing – review and editing. Yasuhisa Fujii: Writing – review and editing. Peter L. Choyke: Supervision; writing – review and editing. Hisataka Kobayashi: Conceptualization; funding acquisition; project administration; supervision; writing – original draft; writing – review and editing.

ACKNOWLEDGMENTS

The authors have nothing to report.

FUNDING INFORMATION

This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (award recipient: Hisataka Kobayashi, grant number ZIA BC 011513).

CONFLICT OF INTEREST STATEMENT

Yasuhisa Fujii is an editorial board member of Cancer Science. The other authors declare no conflicts of interest.

ETHICS STATEMENT

Approval of the research protocol by an Institutional Reviewer Board: N/A.

Informed Consent: N/A.

Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.

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