Awaken Antitumor Immunity: Nanoparticles Act as Messengers

Conventional tumor therapy relies heavily on radiotherapy and chemotherapy that is usually associated with off-target side effects. Additionally, recurrence of many malignancies as well as the prevalence of metastasis further compromises the therapeutical outcomes of radio- and chemotherapy. Lately, immunotherapy has been identified as an effective alternative therapeutic modality. Compared to traditional therapeutical modalities, immunotherapy has several advantages that greatly benefit cancer treatment. First, it capitalizes on the advantages of adaptive and innate immune systems to fight cancer cells. Second, activated immune cells are generally recognizable to tumor-associated antigens enabling precise target of the tumor cells. Third and most importantly, immunotherapy prevents tumor relapse and metastasis via immune memory, thus proving long-lasting anti-tumor immunity. Unfortunately, clinical evidence shows that immunotherapy is only efficacious in some cancer patients due to the poor immunogenicity of most tumors. Thus, developing an efficient strategy for activating anti-tumor immunity to facilitate immunotherapy is urgent.

As signaling molecules tasked with regulating metabolic and physiological functions of organisms, chemical messengers (specifically some metal ions and gaseous molecules) are potential agents for regulating the immune system. However, most chemical messengers exhibit limited regulatory efficiency against tumor growth attributed to the complexity of biological processes. Moreover, cancer cells readily activate antideath pathways to protect themselves from chemical messenger regulation and death. To this end, efficient strategies for anti-tumor immunity activation via chemical messengers are needed to ensure anti-tumor efficacy. Nanomaterial-based cascade engineering is a promising strategy for enhancing therapeutical outcome of different components. It provides intensive correlations between different components to overcome obstacles hence providing nanoplatform with improved performance. However, most cascade engineering research concentrate on reaction cascades, and signaling transduction cascades of chemical messengers have not been fully explored.

Herein, Central South University researchers: Dr. Henan Zhao, Dr. Jianghua Li, Professor Wansong Chen and Professor You-Nian Liu, in collaboration with Professor Liqiang Wang from Zhengzhou University and Professor Ke Zeng from the University of South China, proposed a nanomessenger mediated signaling cascade (ZnPP@PAA-CaS) for regulating anti-tumor immunity. In their approach, the nanomessenger was prepared by first stabilizing CaS nanoparticles using poly(acrylic acid) (PAA) followed by loading zinc protoporphyrin (ZnPP) into porous PAA-CaS nanocomposites. Their work is currently published in the journal, ACS Nano.

The authors found the present nanomessenger gradually released chemical messengers, specifically Ca²⁺ and H₂S, within acidic endosomes of the cancer cells. The synergy between H₂S and Ca²⁺ effectively elevated the intracellular Ca²⁺ stress to induce subsequent tumor cell death. As a messenger amplifier, ZnPP played a vital role in suppressing HO-1 expression to restore the suppressed signaling pathway by preventing the antideath effects of the cancerous cells. Ca²⁺-dependent death of the tumor cells attributed to the signaling transduction cascade effects led to the release of tumor-associated antigens that functioned as in-situ tumor vaccines for activating anti-tumor immunity. This further blocked tumor metastasis and relapse.

In summary, the study presented an innovative ZnPP@PAA-CaS nanomessenger with signaling transduction cascades for efficient regulation of anti-tumor immunity. Both primary tumors and distant metastases were successfully eradicated by the present nanomessenger. The introduction of cascade engineering into chemical messengers is a promising strategy for amplifying cellular regulation and is thus suitable for designing chemical messenger-based therapeutic platforms. In a statement to Advances in Engineering, the authors expressed confidence that the new study findings would contribute to developing future chemical messenger-mediated immunotherapy for effective cancer treatment.