Programing Immunogenic Cell Death in Breast Tumors with Designer DNA Frameworks

Area of Science:

• Biotechnology
• Nanomedicine
• Immunotherapy

Background:

• Cancer treatment faces limitations due to low response rates and severe side effects.
• Current immunotherapies struggle to overcome the 'cold' tumor microenvironment, limiting their efficacy.

Purpose of the Study:

• To develop a multifunctional tetrahedral DNA framework (TDF) for targeted drug delivery and enhanced antitumor immunotherapy.
• To convert 'cold' tumors into 'hot' tumors by inducing immunogenic cell death (ICD) and boosting immune responses.

Main Methods:

• Engineered a TDF loaded with doxorubicin (DOX) and conjugated with RGD peptide for tumor targeting and CpG sequences as an immune adjuvant.
• Investigated the TDF's ability to induce ICD, recruit CD8+ T cells, and upregulate cytotoxic markers (granzyme B, perforin).
• Evaluated the combination therapy of TDF-DOX with α-PD-1 in a bilateral 4T1 mouse model to assess inhibition of primary, distant, and recurrent tumors.

Main Results:

• The multifunctional TDF significantly suppressed 4T1 breast tumor growth by enhancing CD8+ T cell infiltration and cytotoxic protein expression.
• Treatment led to a significant reduction in regulatory T cells (Treg), indicating a shift towards an anti-tumor immune state.
• Combined therapy with α-PD-1 demonstrated remarkable efficacy, inhibiting distant tumor growth by 91.6% and preventing tumor recurrence.

Conclusions:

• The multifunctional TDF serves as an effective drug carrier, reducing chemotherapy side effects through targeted delivery.
• This strategy sensitizes the immune response via ICD, effectively converting 'cold' tumors to 'hot' tumors.
• The TDF-based therapeutic approach shows significant potential for clinical application in improving cancer treatment outcomes.