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<p>Aggressive Oral squamous cell carcinoma (OSCC) remains a major therapeutic challenge due to its high metastatic potential. OSCC with mutated TP53 often exhibits non-functional or gain-of-function p53 variants, elevated anti-apoptotic protein expression and a strongly anti-inflammatory tumor microenvironment. Although tumor regression using folate receptor (FR)-targeted doxorubicin (DOX) conjugated carbon nanospheres has been reported in syngeneic mouse models, the underlying mechanism remained unexplored. In this study, we introduced a novel dual-targeting approach that simultaneously directs therapy toward the tumor and tumor-associated macrophages (TAMs) via FR-mediated delivery. Compared to pristine DOX, FR-targeted delivery resulted in tumor regression and enhanced drug uptake, particularly within the TAM population. Flow cytometry revealed increased CD80 expression with minimal change in CD163, indicating a modest TAM polarization shift toward an anti-tumoral state. A higher CD80/CD163 ratio in FR-targeted groups suggested potential to overcome TAM-linked immune evasion. Collectively, these findings highlight the novel FR-mediated dual-targeting strategy of CSPs as a promising approach to modulate both the tumor and tumor-associated macrophages for improved chemotherapeutic efficacy in aggressive OSCC. This article aligns with SDG-3 (Good Health and Well-Being) of the UN Agenda for Sustainable Development.</p>

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Folate receptor-mediated delivery of doxorubicin modulates tumor-associated macrophages for effective anti-oral cancer therapy

  • 期刊论文

  • 发表日期：

    2026年4月16日

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  • Dwaipayan Bhattacharya,
  • Kalyani Sakhare,
  • Aasia Ansari,
  • Abhiram Kumar,
  • Piyush Khandelia,
  • Rajkumar Banerjee,
  • Kumar Pranav Narayan

摘要

Aggressive Oral squamous cell carcinoma (OSCC) remains a major therapeutic challenge due to its high metastatic potential. OSCC with mutated TP53 often exhibits non-functional or gain-of-function p53 variants, elevated anti-apoptotic protein expression and a strongly anti-inflammatory tumor microenvironment. Although tumor regression using folate receptor (FR)-targeted doxorubicin (DOX) conjugated carbon nanospheres has been reported in syngeneic mouse models, the underlying mechanism remained unexplored. In this study, we introduced a novel dual-targeting approach that simultaneously directs therapy toward the tumor and tumor-associated macrophages (TAMs) via FR-mediated delivery. Compared to pristine DOX, FR-targeted delivery resulted in tumor regression and enhanced drug uptake, particularly within the TAM population. Flow cytometry revealed increased CD80 expression with minimal change in CD163, indicating a modest TAM polarization shift toward an anti-tumoral state. A higher CD80/CD163 ratio in FR-targeted groups suggested potential to overcome TAM-linked immune evasion. Collectively, these findings highlight the novel FR-mediated dual-targeting strategy of CSPs as a promising approach to modulate both the tumor and tumor-associated macrophages for improved chemotherapeutic efficacy in aggressive OSCC. This article aligns with SDG-3 (Good Health and Well-Being) of the UN Agenda for Sustainable Development.