This study introduces a novel molecular targeted cancer therapy called photoimmunotherapy (PIT), which uses a near-infrared (NIR) phthalocyanine dye, IR700, conjugated to monoclonal antibodies (MAb) targeting epidermal growth factor receptors (EGFR). The MAb-IR700 conjugates are activated by NIR light only when bound to the target cell membrane, leading to rapid cell death. This approach minimizes off-target effects and phototoxicity, distinguishing it from conventional photodynamic therapy (PDT). The study demonstrates that MAb-IR700 is highly selective for EGFR-expressing cells, leading to significant tumor shrinkage in vivo. In vitro experiments show that the conjugates bind specifically to the cell membrane, inducing necrotic cell death upon NIR light exposure. The study also confirms that the phototoxic effect is dependent on membrane binding rather than internalization. The MAb-IR700 conjugates were effective in both HER2 and HER1 expressing cells, showing therapeutic effects in A431 and 3T3/HER2 tumors. The study further shows that the conjugates can be used for both therapy and imaging, as they emit diagnostic fluorescence. The results indicate that the MAb-IR700 conjugate is a promising therapeutic and diagnostic agent for cancer treatment, with potential for repeated use due to the low toxicity of NIR light. The study highlights the importance of targeted delivery and the role of reactive oxygen species in phototoxicity, but also suggests that other mechanisms may be involved. The findings suggest that this approach could be applicable to other MAbs, offering a flexible and effective platform for cancer therapy.This study introduces a novel molecular targeted cancer therapy called photoimmunotherapy (PIT), which uses a near-infrared (NIR) phthalocyanine dye, IR700, conjugated to monoclonal antibodies (MAb) targeting epidermal growth factor receptors (EGFR). The MAb-IR700 conjugates are activated by NIR light only when bound to the target cell membrane, leading to rapid cell death. This approach minimizes off-target effects and phototoxicity, distinguishing it from conventional photodynamic therapy (PDT). The study demonstrates that MAb-IR700 is highly selective for EGFR-expressing cells, leading to significant tumor shrinkage in vivo. In vitro experiments show that the conjugates bind specifically to the cell membrane, inducing necrotic cell death upon NIR light exposure. The study also confirms that the phototoxic effect is dependent on membrane binding rather than internalization. The MAb-IR700 conjugates were effective in both HER2 and HER1 expressing cells, showing therapeutic effects in A431 and 3T3/HER2 tumors. The study further shows that the conjugates can be used for both therapy and imaging, as they emit diagnostic fluorescence. The results indicate that the MAb-IR700 conjugate is a promising therapeutic and diagnostic agent for cancer treatment, with potential for repeated use due to the low toxicity of NIR light. The study highlights the importance of targeted delivery and the role of reactive oxygen species in phototoxicity, but also suggests that other mechanisms may be involved. The findings suggest that this approach could be applicable to other MAbs, offering a flexible and effective platform for cancer therapy.