Reversing insufficient photothermal therapy-induced tumor relapse and metastasis by regulating cancer-associated fibroblasts

Abstract

Insufficient tumor accumulation and distribution of photosensitizers as well as low antitumor immunity severely restrict the therapeutic efficacy of photothermal therapy (PTT). Cancer-associated fibroblasts (CAFs) play a key role in tumor extracellular matrix (ECM) remodeling and immune evasion. Reshaping tumor microenvironment via CAF regulation might provide a potential approach for complete tumor elimination in combination with PTT. Here, tumor cell-derived microparticles co-delivering calcipotriol and Indocyanine green (Cal/ICG@MPs) are developed to modulate CAFs for improved PTT efficacy. Cal/ICG@MPs efficiently target tumor tissues and regulate CAFs to reduce tumor ECM, resulting in enhanced tumor accumulation and penetration of ICG to generate strong PTT efficacy and activate CD8+ T cell-mediated antitumor immunity. In addition, Cal/ICG@MPs-triggered CAF regulation enhances tumor infiltration of CD8+ T cells and ameliorates CAF-induced antigen-mediated activation-induced cell death of tumor-specific CD8+ T cells in response to PTT, eliciting long-term antitumor immune memory to inhibit tumor recurrence and metastasis. Our results support Cal/ICG@MPs as a promising drug to improve PTT efficacy in cancer treatment.

Targeting the tumor stroma for cancer therapy

“…Specifically, VDR servers as a master genomic suppressor of pancreatic stellate cells (PSC) activation state and has the potential to revert PSCs into quiescent state. In this context, calcipotriol destroyed several tumor-supporting signaling pathways and enhanced the effects of chemotherapy in multiple mouse tumor models, which hindered the tumor-stroma interplay and tumor proliferation [439][440][441][442]. Some vitamin D analogues (e.g.…”

Antitumor Applications of Photothermal Agents and Photothermal Synergistic Therapies

“…PTAs are injected into the body, and, using targeting technology, they accumulate near tumor tissue, where they damage the protein structure of tumor cells, resulting in a cure. PTT has the advantage of being able to use variable levels of external laser irradiation to precisely target the tumor while avoiding harm to the surrounding healthy tissue; it can also be used to treat all types of cancer and is non-invasive [ 24 , 25 , 26 ].…”

Hyperthermia-induced stellate cell deactivation to enhance dual chemo and pH-responsive photothermal therapy for pancreatic cancers

“…3,16 In contrast, photothermal therapy (PTT) produces hyperthermia without oxygen consumption, and therefore, could efficiently ablate cancer cells and regulate TME under exogenous light irradiation. 17,18 It is also observed that hyperthermia diffusion from tumors and the unwanted accumulation of PTT agents in normal tissues could result in nonspecific damages to healthy cells. 19 To circumvent this problem, researchers innovated activatable PTT paradigms, such as tumoral acidic pH-activated PTT for cancer treatment, and demonstrated that these paradigms are quite effective in executing cancers while avoiding damage to normal tissues.…”